Allergy

BackgroundPeanut allergies continuously present urging public health challenges. Oral immunotherapy (OIT) is an important treatment option for peanut allergies, but its effectiveness varies, in terms of inducing desensitization (DS) or achieving long-term sustained unresponsiveness (SU). Identifying biomarkers to predict OIT outcomes is thus of great translational interests. MethodsWe thoroughly analyzed data from the POISED trial and our in-house OPIA trial, with a particular focus on the peanut-reactive T cells, in an attempt to identify potential biomarkers at baseline before OIT to distinguish DS and SU outcomes. ResultsIn both the POISED trial and OPIA trial, we found that functional profiles of peanut-reactive T cells at baseline before OIT, such as their type II T helper (Th2) cell cytokine productions, including IL-4, were associated with the DS versus SU outcomes after OIT cessation. ConclusionsBaseline peanut-reactive T cell functional profiles might provide new possibilities for biomarker discovery to predict peanut allergy OIT outcomes.

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.

BackgroundAtopic dermatitis (AD) is a common atopic disease worldwide and dupilumab, a monoclonal antibody directing to the IL4/IL13 signalling, is emerging as an effective therapy for AD. Recently, there is report describing differences in AD severity and treatment responses to dupilumab among different geographic regions, but the underlying mechanisms remain unresolved. Patients ancestral backgrounds represent one of the key differences among various geographic areas. Their implications in variability regarding diseases and treatment responses are gaining more and more recognitions. MethodsWe aimed to delineate the potential ancestry-associated differences in AD and treatment responses to dupilumab. We thoroughly surveyed Gene Expression Omnibus (GEO) for transcriptomic dataset in the context of AD and dupilumab treatment involving individuals of diverse ancestral backgrounds and carried out comparative analyses for samples from different ancestral groups. ResultsOnly one transcriptomic dataset was found for biopsy specimens from lesion and non-lesion skin from AD patients of self-reported White and Asian ancestral backgrounds. Despite comparable clinical phenotypes, Gene Set Enrichment Analysis revealed that skin samples from White AD patients exhibited upregulated IL4 & IL13 signalling from baseline to up to 4-week post dupilumab treatment, relative to Asian ones. ConclusionsThis is the first study of its kind to unravel the ancestry-related differences in AD and dupilumab treatment responses. These findings might be instrumental to future clinical patient stratification, risk assessment and guide personalized medicine treatment options for dupilumab.

ObjectivesMaternal hypertensive disorders (MHD) are widespread globally, modifying maternal and fetal immunity, and have been linked to increased allergic diseases in offsprings. Nevertheless, so far, most studies in this field are small-scale and results remain inconclusive. MethodsHarnessing unprecedented global allergic disease and pregnancy data covering more than 150 countries from 1990 to 2019 as proxies, we leveraged the state-of-the-art generalized additive model (GAM) to interrogate the potential link between MHD and common offspring allergic diseases, exemplified by atopic dermatitis (AD) and asthma. ResultsA model considering the main effects from MHD, socioeconomic factor like GDP and time, as well as their interactions was favoured, suggesting their interactive effects on offspring allergic diseases. Generally, MHD in pregnancies were associated with increased AD and asthma in offsprings early in life, and a more pronounced effect was found for AD relative to asthma. ConclusionsGlobally, MHD in pregnancies are linked to increased offspring allergic disease burden, which, with further in-depth investigations, would inform allergic disease preventions in clinic. Our analyses also support the Developmental Origins of Health and Disease (DOHAD) concept and showcase a novel methodology for DOHAD-related research.

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.

Recent biobank based exon sequencing studies included thousands of traits while the mutational spectrum of asthma and allergy associated genes is still unknown. MethodsMeta-analysis of exome data from 281,104 UK Biobank samples that were analyzed for association of mostly rare variants with asthma, allergic rhinitis and atopic dermatitis. Variants of interest (VOI) were tabulated, shared genes annotated and compared to earlier GWAS, WGBS, WES and selected candidate gene studies. Results354 VOI were significantly associated with the traits examined. They cluster mainly in two large regions on chromosome 6 and 17 while there is basically no overlap of atopic dermatitis with both other diseases. After exclusion of the two atopic dermatitis variants, 321 unique VOI remain in 122 unique genes. 30 genes are shared by the group of 87 genes with increased and the group of 65 genes with decreased risk for allergic disease. 85% of genes identified earlier by common SNPs in GWAS can not be replicated. DiscussionMost identified genes are involved in interferon {gamma} and IL33 signaling pathway. They highlight already known but also new pharmacological targets, including the IL33 receptor ST2/IL1RL1, TLR1, ALOX15, GSDMA, BTNL2, IL13 and IKZF3. Future pharmacological studies will need to included these VOI for stratification of the study population.

BackgroundGastroenteric tract requires robust tolerogenic mechanisms to tolerize foreign antigens like foods and microbiota. This is critical to establish the immune homeostasis, which upon disruption, might contribute to a plethora of atopic disorders, including food allergy and eosinophilic esophagitis (EOE). Recently, there was a new subset of tolerizing dendritic cells (tolDCs), PRDM16 tolDC, discovered in the gut of mice and humans, which confers protection against food allergy. Whether an analogous population of it exist in the esophagus is unknown, especially in the context of EOE, another atopic disease associated with dietary antigens. MethodsWe thoroughly analyzed the human esophagus cell atlas single cell RNA-seq dataset and the myeloid DC-VERSE dataset, in an attempt to identify and characterize the esophageal counterpart of the intestinal PRDM16 tolDC. ResultsWe identified the esophageal counterpart of intestinal PRDM16 tolDC as a conventional type II DC subtype expressing PRDM16, termed as cDC2C (PRDM16). We demonstrated the similarities between PRDM16 tolDC and cDC2C (PRDM16) regarding their transcriptomic and functional profiles. Importantly, we found that cDC2C (PRDM16) were expanded during EOE and exhibited an anti-inflammatory phenotype, suggesting their protective role in EOE. Notably, these tolerogenic DCs were not found in other atopic diseases beyond the gastroenteric tract. ConclusionsWe here defined a novel tolerogenic DC population in human esophagus and demonstrated their implications in the pathophysiology of EOE. These findings would provide novel insights towards the tolerogenic mechanisms along the gastroenteric tract and possess translational relevance for EOE diagnosis and interventions.

BackgroundIncreasing evidence showed that seasonal allergic rhinitis (SAR), as an allergy disease, could be alleviated with traditional Chinese medicine (TCM) formula, one example being Tuomin Zhiti Decoction (TZD). However, as a complex composition of TCM herbs, the mechanism of TZD in the treatment of SAR remain unclear. PurposeUncover the mechanism of TZD for treating SAR based on computational analysis and clinical multi-omics experiments. Study designIntegrate computational analysis including network target analysis and machine learning algorithms with clinical multi-omics experiments and public omics data. MethodsBy analyzing TZDs composition through a network-based method, we identified the biological effects of each compound, constructing a comprehensive biological network to elucidate TZDs molecular and pathway mechanisms against AR. Single-arm clinical trials on the gut microbiome and serum transcriptomics corroborated our computational insights. Further validation through public omics data highlighted key TZD compounds, paving the way for future research. ResultsTZD was discovered to exert a regulatory effect on various modules associated with AR, as demonstrated by the constructed biological network. Insights from gut microbiome and serum transcriptomics in clinical trials, where immune-related microbiomes represented by Prevotella, as well as pathways and biological processes including antigen processing and presentation, activation and regulating immune cell surface receptor, were markedly enriched (P value < 0.05), indicated that TZD played a pivotal role in modulating immune processes and the immune cells against AR. With the verification of multi-omics, it was determined that TZD potentially influences immune responses and downstream immune cells like CD4+ T cells, through both direct mechanisms involving antigen and indirect mechanisms mediated by gut microbiomes in the treatment of AR. ConclusionThrough combination of computational prediction and analysis together with clinical multi-omics, a network target based framework provided a new insight for uncovering the mechanism of TZD for treating AR.

Peanut allergy poses a significant global health concern, triggering hypersensitivity reactions upon exposure to peanuts. Understanding the molecular mechanisms governing peanut-specific immune responses is imperative for developing effective therapeutic approaches. This study aimed to investigate differentially expressed genes (DEGs) and associated molecular pathways implicated in peanut allergy-induced immune responses. Employing a systematic and bioinformatics-driven approach, we analyzed gene expression profiles from peanut-allergic individuals and healthy controls using RNAseq Next-Generation Sequencing (NGS) data. Enrichment analysis of DEGs revealed their involvement in various inflammatory conditions, including autoinflammatory, allergic, and respiratory disorders. Additionally, pathway enrichment analysis highlighted perturbed molecular pathways such as Asthma, IL-17 signaling pathway, and Inflammatory bowel diseases, underscoring their role in modulating peanut-specific immune responses. Protein-protein interaction network analysis identified central regulatory hubs, elucidating the intricate molecular interplay underlying the immune response to peanut allergens. Overall, our findings offer comprehensive insights into the molecular landscape of peanut allergy, delineating key DEGs and pathways associated with peanut-specific immune responses. This systematic and bioinformatics-driven approach enhances our understanding of allergic reactions to peanuts, providing potential targets for the development of novel therapeutic interventions and diagnostic biomarkers for peanut allergy management.

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.

Allergen-specific immunotherapy (AIT) is the only disease-modifying treatment currently available to treat allergy. However, it has limitations, as most allergens are poorly immunogenic, resulting in an AIT process that can take years. Therefore, adjuvant selection becomes critical to achieve a more efficacious therapy. Our group has developed and tested an amphiphilic TLR7/8 agonist (IMDQ) and a RIG-I agonist (SDI) that used alone, or in combination, have demonstrated strong adjuvant activity for influenza and SARS-CoV-2 vaccines in preclinical models. Here we describe the effect of these adjuvants in the sensitization of preclinical models with the ovalbumin (OVA) asthmatic allergic model via an in-depth humoral and cellular immune profiling. We assess their immune skewing and tolerance inducing capacities in previously sensitized preclinical models with different genetic backgrounds (C57BL/6 vs. BALB/c mice). Moreover, we evaluate their effect in an unrelated antigenic challenge with influenza. Finally, we investigate the role of IgG subclasses and T-cell subpopulations in the protection against OVA challenge conferred by the combination of IMDQ and SDI. We demonstrate that OVA-immunization in combination with IMDQ+SDI prevents allergic sensitization via the induction of a balanced Type 1/Type 2 response. Furthermore, it can revert the allergic phenotype in mice previously sensitized with OVA-Alum, through reducing lung eosinophilia, as well as IL-4 and IL-5 production. However, this was dependent on genetic background. IMDQ+SDI sensitization also led to reduced morbidity of a secondary influenza challenge in OVA-sensitized mice. Finally, we demonstrated that IgG2c, by itself, cannot protect from allergic sensitization and that both CD4+ and CD8+ T-cells are needed for IMDQ+SDI prevention of eosinophil recruitment and activation upon intranasal OVA-challenge.

Asthma is one of the most common chronic diseases globally. There are various risk factors for asthma, including respiratory infections, like rhinovirus and respiratory syncytial virus infections. Nevertheless, impacts from non-respiratory tract infections on asthma remain unresolved. Globally, enteric infections are the most common infections. Their target organ, the intestinal system, shares the same embryonic origin, the endoderm, as the respiratory tract. These led us to inspect the potential associations between enteric infections and asthma. We analyzed three independent epidemiological datasets with the cutting-edge generalized additive model (GAM). Consistently, in two regional datasets (America and Japan) and a global dataset, we found that enteric infection incidence was generally linked to increased asthma disease burden. This is the first study to our knowledge to comprehensively elucidate the positive associations between enteric infections and asthma. Our findings would be instructive to both clinical practice and mechanistic study for asthma.

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

IntroductionThe aims of presenting study were trying to expose the course of SARS-CoV-2 (severe acute respiratory syndrome-related coronavirus) in patients with allergic rhinitis (AR), to compare the prevalence of SARS-CoV-2 infection, hospitalization and pneumonia rates in patients with AR receiving allergen immunotherapy (AIT) and patients did not receive AIT (non-receivers) and to define possible risk factors for SARS-CoV-2 positivity in patients with AR. Materials and MethodsA total of 419 patients with AR who were being followed up in a tertiary allergy clinic between 1 June 2020 and 31 December 2020, were selected for the study. Only patients who were receiving active-continuous treatment for allergic rhinitis during the study period, were included in the study. ResultsSeventy-nine patients (18.9%) became infected with the SARS-CoV-2 [32 patients (19.6%) in AR patients with AIT and 47 patients (19.0%) in non-receivers] and the rate of pneumonia was 2.4% [12.7% of SARS-CoV-2 (+) patients]. There was no significant difference was determined between the AR patients with AIT and the non-receivers in regard to the rate of SARS-CoV-2 infection, pneumonia, and hospitalization (p: 0.864, p: 0.081, p: 0.113). There was a significant difference between the groups in terms of gender, duration of disease, sensitivity to allergens (atopy), and serum IgE levels (p: 0.009, p: 0.001, p: 0.001, and p: 0.001). The accompanying comorbidities, eosinophil count, AIT, and duration of AIT were not found to be associated with an increased risk SARS-CoV-2 PCR positivity. However, the female gender was shown to be associated with a decreased risk for SARS-CoV-2 PCR positivity (OR, 0.571; 95% confidence interval, 0.330-0.987; p: 0.045) ConclusionThe course of SARS-CoV-2 is similar in patients with AR who underwent AIT and patients with AR who did not undergo AIT, and AIT does not seem to increase the risk for SARS-CoV-2 infection.

BackgroundTick bites often promote local allergic reactions in the skin and predispose to red meat allergy. The mechanisms involved in these processes are not fully understood. Here we investigated the local changes to the skin and intestine induced by tick bites. MethodsC3H/HEN or Balb/c mice were subjected to either tick bites by Ixodes ricinus (I. ricinus) or mechanical skin injury. Skin or intestine was analyzed a different time point by transcriptomic and histological techniques. ResultsOur results indicate that I. ricinus bites promote epidermal hyperplasia, spongiosis and an accumulation of eosinophils and mast cells in the bitten skin. In addition, I. ricinus bites promote the expression of genes and activate pathways also induced by mechanical skin injury elicited by tape stripping. Remarkably, similar to tape stripping, I. ricinus bites promote an increase in total serum IgE, and intestinal tuft cell and mast cell expansion. ConclusionI. ricinus bites in mice promote cutaneous inflammation that resembles allergic skin inflammation, as well as intestinal changes that could play a role in the predisposition to red meat allergy.

Withdrawal StatementThe authors have withdrawn this manuscript owing to inaccuracies in the calculation of tuft cell numbers and errors in the selection of immunofluorescence images used to support our claims. Therefore, the authors do not wish this work to be cited as reference for the project. If you have any questions, please contact the corresponding author.

BackgroundAmong the members of the Transient Receptor Potential (TRP) family, TRPV1 is distinguished as the primary receptor involved in thermal pain perception, closely associated with temperature changes. Acting as a critical nociceptor and thermosensitive receptor, TRPV1 is pivotal in the domain of allergic diseases. Despite its significance, there is a discernible lack of comprehensive reviews exploring the interactions between TRPV1 and allergic conditions in the academic literature. This study aims to thoroughly examine the relationship between TRPV1 and allergic diseases using bibliometric and visual analysis techniques. Our goal is to uncover the mechanisms by which TRPV1 influences allergic diseases, providing a robust scientific basis for future research directions and potential therapeutic strategies. MethodsTo investigate the relationship between TRPV1 and allergic diseases, we conducted a comprehensive search in the Web of Science (WoS) database. We employed a suite of analytical tools, including Excel, the WoS online analysis platform, the bibliometrix package in R, and CiteSpace software. These tools facilitated the systematic organization, detailed description, and thorough analysis of the retrieved literature, using co-citation, co-authorship, and co-occurrence visualizations to identify significant patterns and trends. ResultsThis bibliometric analysis encompassed 1,045 articles on TRPV1 and allergic diseases, published by researchers from 57 countries and 1,179 institutions across 369 journals. Publication output remained low until 2008, after which it grew steadily, peaking at 70 articles in 2020. The United States contributed the most publications, followed by China and the United Kingdom. Johns Hopkins University emerged as a central collaborative hub, with Bradley Joel Undem as the most prolific author (30 publications). The most cited study, by Cevikbas et al., explored TRPV1/TRPA1 involvement in T-cell dependent itch. Recent research focuses on mechanisms such as neurogenic pain, itch, sensitization, oxidative stress, and atopic dermatitis, frequently employing mouse models. ConclusionThis study provides a detailed analysis of research characteristics, emerging trends, and future directions in the study of TRPV1 and allergic diseases, offering an objective overview of global contributions in this field. It delivers critical insights to inform future investigations on TRP channels and allergic conditions. As an essential thermosensitive receptor, TRPV1 plays a central regulatory role in allergic diseases, with recent research increasingly directed towards developing animal models and clarifying activation mechanisms. Future research is expected to explore the complexities of sensitization mechanisms and receptor expression more deeply.Given its critical role, TRPV1 stands out as a promising pharmacological target for allergic rhinitis, meriting further study and potential therapeutic development. This focus on TRPV1 could lead to novel interventions that improve management and treatment outcomes for allergic conditions.

A substantial number of patients with newly onset of chronic urticaria was observed rapidly after the booster vaccine against COVID-19. This observation was unprecedented compared to the primary series of vaccination. To address this concern, we initiated an online observational study with the help of local allergists. We found a striking association between the booster dose, the Moderna vaccine, and the new onset of chronic urticaria within the following 10 days. These data were confirmed when reviewing all cases of CSU related to COVID-19 vaccination reported to Swissmedic, the Swiss regulatory agency. These data should not discourage patients from being vaccinated, as this vaccination campaign has been instrumental in reducing COVID-19 burden and preventing millions of deaths. Yet, there is an urgent need to establish appropriate guidelines and monitor this adverse event more closely, considering that a fourth dose is currently being administered.

BackgroundThe incidence of lung allergies is reduced in countries with higher prevalence of infection and environmental exposure to microbes. However, enteric bacterial infections do not always correlate with lower incidence of allergic disorders and how lung immunity to allergens can be regulated by gut exposure to pathogens and their toxins is not fully understood. ObjectiveWe used mouse models of enterotoxigenic Escherichia coli (ETEC) infection and lung allergy to examine how gut exposure to bacteria, or their related toxins, affects allergic lung inflammation. MethodsNaive C57BL/6 mice were infected with enterotoxigenic Escherichia coli (ETEC) or orally treated with the ETEC LT toxin, to mimic enteric bacterial infections. After two weeks, these mice were treated intranasally with Ovalbumin (OVA) and Papain or IL-33, followed by challenge with OVA, to induce allergic lung inflammation that was assessed using multiple readouts. ResultsGut exposure to ETEC significantly inhibited allergic lung inflammation in a LT-dependent manner, as demonstrated by reduced tissue inflammation, less accumulation of type 2 cytokines, and reduced lung numbers of type 2 immune cells such as type 2 innate lymphoid cells (ILC2) and eosinophils. The anti-allergic capacity of LT was associated with reduced ability of lung ILC2s to recognize IL-33. Counterintuitively, deletion of either IL-33 or ILC2s significantly reverted the LT protective effect, suggesting the LT-mediated protection may occur through gut release and local sensing of IL-33. ConclusionsExposure to ETEC protects hosts against allergic lung inflammation through a negative feedback loop regulated by gut IL-33 release and sensing, suggesting a possible new immunological mechanism for reduced lung allergy incidence observed in areas with enteric bacterial infections. Key Messages- Enteric exposure to enterotoxigenic E. coli (ETEC) bacteria or its toxin LT significantly protects hosts against lung type 2 allergic inflammation. - ETEC and LT downregulate the capacity of lung ILC2s to respond to allergen-induced IL-33. - Deletion of IL-33 or ILC2s significantly impairs the protective effect of ETEC and LT, suggesting the presence of a negative feedback loop driven by toxin-induced gut IL-33 release.

Dendritic cells (DC) play a crucial role in regulating allergic asthma. We have demonstrated that the absence of semaphorin3E (Sema3E) exacerbates asthma features in acute and chronic asthma models. However, the role of plexinD1 in these events, especially in DC is unknown. Therefore, we investigated the role of plexinD1 in CD11c+ DC in the HDM model of asthma. CD11c+ DC-specific plexinD1 knockout mice and wild-type mice were subjected to HDM acute allergen protocol. Airway hyperresponsiveness (AHR) parameters were measured using the FlexiVent ventilator. Lung tissue and bronchoalveolar lavage fluid (BALF) were processed by flow cytometry. Cytokines and antibodies were measured using mesoscale and ELISA. Collagen deposition and mucus production were visualized by histological staining, and associated genes were investigated using Real-time PCR. We showed that DC-specific plexinD1 knockout mice exhibited exacerbated airway hyperresponsiveness, including increased airway resistance and tissue elastance. These mice displayed enhanced levels of mucus production and collagen gene expression compared to wild-type mice. These events were accompanied by enhanced recruitment of conventional DCs, specifically CD11b+ cDC2, into the lungs and higher levels of total and HDM-specific serum IgE in CD11cPLXND1 KO compared to wild-type counterparts. Mechanistically, a significantly higher level of IgE in the co-culture of B-DCs isolated from CD11cPLXND1 KO mice compared to DCs isolated from wild-type mice. Overall, our data reveals that the Sema3E-plexinD1 signalling pathway in CD11c+ DC is critical in modulating asthma features. Graphical Abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=140 SRC="FIGDIR/small/557276v1_ufig1.gif" ALT="Figure 1"> View larger version (29K): org.highwire.dtl.DTLVardef@170c121org.highwire.dtl.DTLVardef@1979dddorg.highwire.dtl.DTLVardef@fd547borg.highwire.dtl.DTLVardef@1b5726a_HPS_FORMAT_FIGEXP M_FIG C_FIG