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.

BackgroundOral immunotherapy (OIT) is an important treatment option for food allergy but achieving sustained unresponsiveness (SU) via OIT is challenging. Improving SU for OIT with adjuvants is of great interest but little progress has been made so far. Gut microbiota-derived metabolites like short-chain fatty acids (SCFAs) protect against food allergy in mouse models via promoting regulatory T cells (Treg) generation. We thus aim to investigate the impacts from metabolite-based dietary supplement as an adjuvant in food allergic children receiving peanut OIT. MethodsBased on a prior phase 2 single centre open label interventional randomized controlled trial Oral Peanut Immunotherapy with Short Chain Fatty Acid Adjuvant (OPIA, ACTRN12617000914369), gut microbiota and immune profiles from food allergic children receiving peanut OIT supplemented with butyrylated high-amylose maize starch (HAMSB) or with low amylose maize starch (LAMS) were comprehensively profiled. ResultsHAMSB conferred minimal effects on gut microbiota, except transiently increasing their SCFA production like propionate and butyrate. HAMSB skewed CD4+FOXP3+ Treg towards a tolerogenic phenotype and strikingly increased anti-inflammatory CD4-FOXP3+ Treg, even after cessation of OIT and HAMSB. ConclusionsWe present the first report of the potent immune modulatory effects of dietary butyrate supplementation via HAMSB over an extended period of 1 year in food allergic children. Our findings highlight the tolerance inducing effects of HAMSB and its potential as immunotherapy adjuvant for food allergy and/or autoimmune diseases.

BackgroundMisdiagnosis of peanut allergy is a significant clinical challenge. Here, a novel diagnostic blood-based test using a Bead-Based Epitope Assay ("peanut BBEA") has been developed on the LEAP cohort and then independently validated on the CoFAR2 and POISED cohorts. MethodsDevelopment of the peanut BBEA followed the National Academy of Medicines established guidelines with discovery performed on 133 subjects from the non-interventional arm of the LEAP trial and an independent validation performed on 81 subjects from the CoFAR2 study and 84 subjects from the POISED study. All subject samples were analyzed using the BBEA methodology. The peanut BBEA test measures levels of two Ara h 2 epitopes and compares their combination to a pre=specified threshold. If the combination of the two epitope levels is at or below the threshold, then the subject is ruled "Not Allergic", otherwise the subject is ruled "Allergic". All allergic diagnoses were OFC confirmed and subjects ages were 7-55 years. ResultsIn validation on the CoFAR2 and POISED cohorts, the peanut BBEA test had a combined sensitivity, specificity, positive predictive value, negative predictive value, positive likelihood ratio, negative likelihood ratio and accuracy of 91%, 95%, 95%, 91%, 18.2, 0.09 and 93%, respectively. ConclusionThe peanut BBEA test performance in validation demonstrated overall high accuracy and compared very favorably with existing diagnostic tests for peanut allergy including skin prick testing, peanut sIgE and peanut component testing.

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.

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.

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.

BackgroundEarly peanut (PN) introduction may prevent peanut allergy in at-risk children. Little data exists regarding early introduction for infants with large skin prick tests (SPT) or high peanut IgE levels, who are not often offered oral food challenges (OFC). ObjectiveTo retrospectively assess tolerance of a low dose (1 gram) of peanut in infants at risk for peanut allergy, including highest-risk infants (HRI) with SPT wheal >7mm. MethodsWe reviewed PN OFCs performed over a two-year period at our pediatric allergy center. Low-dose PN OFC was offered to all infants considered at risk for PN allergy, regardless of peanut SPT or IgE results. Dosing was escalated after OFC at home. ResultsOf infants with SPT wheal <=4 mm (n=30), 29 (97%) were low-dose-tolerant. Of those with SPT >4 mm (n=40), 25 (63%) were low-dose-tolerant, and Ara h2 IgE was significantly lower compared to non-tolerant individuals (median 0.62 versus 6.49 kU/L, p<0.05). Among HRI with SPT >7mm (n=22), 12 (55%) were tolerant, with median SPT 9mm (range 8-11mm), PN-IgE 1.1 kU/L (0.3-10.7 kU/L) and Ara h2 1.6 kU/L (0-9.57 kU/L). Age, sex, race, eczema, and egg sensitization did not affect tolerance regardless of SPT size. After 3-6 months, most infants tolerant at OFC were gradually able to consume larger doses of PN. ConclusionMany infants with PN-SPT >4mm are tolerant of low-dose peanut, and Ara h 2 IgE may be predictive for clinical tolerance among these infants. Low-dose PN-OFC with gradual updosing may help prevent PN allergy in a greater number of at-risk infants.

IntroductionThe atopic march refers to the natural history of the sequential development of atopic dermatitis (AD), food allergy (FA), asthma and allergic rhinitis (AR) in childhood, but there is significant heterogeneity in the timing and order of disease presentation. Eosinophilic esophagitis (EoE) is an emerging food-induced inflammatory disease of the esophagus that shares clinical and immunologic features, genetic susceptibility and comorbidities with other march members. We sought to investigate the incidence and prevalence of EoE in a cohort of children with AD and elucidate the individual trajectories of sensitization and allergic comorbidity development. MethodsWe evaluated 700 children participating in the Mechanisms of Progression of Atopic Dermatitis to Asthma in Children (MPAACH) cohort. FA was defined as parental report of a physician diagnosis. AR was defined by a positive skin prick test to [&ge;]1 aeroallergen and symptoms. Asthma was defined by pulmonary function testing and symptoms according to ATS criteria. Participants were classified as having EoE if they had [&ge;]15 eosinophils per high-power field in at least one esophageal biopsy. ResultsOf the 700 children in MPAACH, 10 developed EoE, all after AD onset. The cumulative incidence of EoE in MPAACH was 0.7% by age 2, 0.7% between ages 2 and 5, and 1.6% between ages 5 and 8. The prevalence of EoE in MPAACH is 1.4% (95%CI 0.5-2.3%) and the median age at EoE diagnosis was 3.7 years (interquartile range (IQR): 1.8-6.5). Despite no difference in skin barrier quality or AD severity, children with EoE were more likely to have food sensitization (60% vs. 28%, p=0.039) and FA (70% vs. 13%, p<0.001). 90% of children with EoE had [&ge;]1 allergic comorbidity compared to 49% of the MPAACH cohort (p=0.009). Of these 9, 6 developed FA and/or AR prior to their EoE diagnosis and 3 children developed FA, AR, and/or asthma after EoE onset. ConclusionsOur data support the inclusion of EoE as a fifth member of the march, with new incidence estimates showing enrichment in children with AD, underscoring early-life AD as a risk factor for EoE. The higher prevalence of food sensitization and FA despite no difference in skin barrier quality or AD severity suggests the esophagus as the site of allergen penetration independent of the skin. These data support screening for EoE symptoms in children with early allergic manifestations.

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.

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

As research in the field of food allergy is gaining momentum with new and emerging therapies there is need for both researchers and clinicians to have a better understanding on how to put all this new information into context in clinical care. We are continuously learning from other fields, such as oncology, that a one-shoe-fits all type approaches are becoming the practice of the past and there is need to incorporate markers of disease activity as well as drug selection into clinical care. In the United States, this can happen in two ways; laboratory developed testing and companion diagnostics, generally former leading the path to the later. The findings in this letter is a collaboration between four CLIA/CAP accredited in-office flow cytometry laboratories in Utah, New York and Virginia that are part of very busy food allergy clinics directed by board certified Allergist/Immunologists. The identification of changes in basophils and B cells during oral food immunotherapy are proving to be potentially useful markers in monitoring these patients. We show a high ratio of CD63 to CD203c and CD73 expression on B-cells, compared to healthy non-allergic controls and patients who have outgrown their food allergies. This ratio of basophil surface markers as well as B cell CD73 expression drops as patients are undergoing food-OIT. Quite interestingly, we see a similar low pattern in patients who have non-releaser basophils. Altogether these biomarkers are providing useful and important information monitoring patients and we have validated these assays for clinical use as laboratory developed tests. The Basophil Activation Test is used much more routinely outside the United States, and the powerful correlation it provides to oral food challenge outcomes is making it a very attractive tool. We have just submitted two manuscripts on the validation of the BAT as well as sample stability which is under review elsewhere. We expect more utility of the BAT in the United States in the future. Incorporating biomarkers to clinical care of patients with food allergies will provide to be important in assessing efficacy as well as complications of various therapies as well as monitoring the natural resolution of the food allergies.

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.

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.

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.

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.

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

ABTRACTO_ST_ABSBackgroundC_ST_ABSAtopic dermatitis (AD) is a heritable and heterogeneous inflammatory chronic skin disorder. Utilizing decision tree/supervised learning of extensive clinical, molecular and genetic data, we aimed to define distinct AD endotypes. MethodsDeep phenotyping and whole-genome sequencing was performed on samples obtained from participants of EPIONE, a randomized-controlled phase III study in AD patients with severe pruritus comprising mild (23%), moderate (64%) and severe (13%) AD as determined by AD Investigator Global Assessment scale. Three categories of analysis were performed: clinical associations, lab value associations (EOS, IgE, cytokines) and genetic analysis of whole-genome sequencing data ResultsBased on a decision tree, we found that five clinical features from the SCORing Atopic Dermatitis (SCORAD) Index can accurately differentiate between IGA severities. We observe a significant difference between severity and eosinophil counts (p<0.001), IgE (p<0.001) and Filaggrin (FLG) LOF frequency (OR 2.3, CI 1.6-3.2, p<0.0001) as well as interleukin pathway genes, specifically IL5RA variants differentiating the groups. ConclusionOur results suggest significant differences between severity groups across a number of features appear to constitute distinct endotypes with likely distinct causative factors. Differing underlying pathophysiologys indicate endotype knowledge is critical to help guide therapeutic approaches to AD. Capsule summaryO_LIAD is a heritable and heterogeneous skin disorder that makes the one size fits all therapeutic approach suboptimal for patients with AD. C_LIO_LIWe attempted to define AD endotypes based on clinical, molecular, and genetic characteristics. Clinical, CBC, and genetic associations all tend to suggest existence of separate endotypes. C_LI

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.

Peanut Oral Immunotherapy (POIT) holds promise for remission of peanut allergy, though treatment is protracted and successful in only a subset of patients. Because the gut microbiome is linked to food allergy, we sought to identify fecal microbial predictors of POIT efficacy and to develop mechanistic insights into treatment response. Longitudinal functional analysis of the fecal microbiome of children (n=79) undergoing POIT in a first double-blind, placebo-controlled clinical trial, identified five microbial-derived bile acids enriched in fecal samples prior to POIT initiation that predicted treatment efficacy (AUC 0.71). Failure to induce disease remission was associated with a distinct fecal microbiome with enhanced capacity for bile acid deconjugation, amino acid metabolism, and increased peanut peptide degradation in vitro. Thus, microbiome mechanisms of POIT failure appear to include depletion of immunomodulatory secondary bile and amino acids and the antigenic peanut peptides necessary to promote peanut allergy desensitization and remission.