Global associations of macronutrient supply and asthma disease burden Duan Ni1,2,3, Alistair M. Senior3,4,5, David Raubenheimer3,4, Stephen J. Simpson3,4, Laurence Macia3,6,7, Ralph Nanan1,2,3,*1 Sydney Medical School Nepean, The University of Sydney, Sydney, NSW, Australia2 Nepean Hospital, Nepean Blue Mountains Local Health District, Sydney, NSW, Australia3 Charles Perkins Centre, The University of Sydney, Sydney, NSW, Australia4 School of Life and Environmental Sciences, The University of Sydney, Sydney, NSW, Australia5 Sydney Precision Data Science Centre, The University of Sydney, Sydney, NSW, Australia6 School of Medical Sciences, Faculty of Medicine and Health, The University of Sydney, Sydney, NSW, Australia7 Sydney Cytometry Core Research Facility, Charles Perkins Centre, The University of Sydney and Centenary Institute, Sydney, NSW, Australia* Correspondence:Ralph [email protected] Medical School Nepean, The University of Sydney.Nepean Hospital, Level 5, South Block, Penrith NSW, 2751, AustraliaTelephone: +61 2 4734 1614Fax: +61 2 4734 1144To the Editor,We read with interest the work by Shin et al. 1, investigating the global disease burden of allergic disorders. They showed that the age-standardized prevalence of asthma has decreased over time on a global level.Following a similar theme, we curated asthma disease burden, macronutrient (protein, carbohydrate and fat) supply and gross domestic product (GDP) data around the globe (Supplementary Methods). Our analysis found that in parallel to changes in asthma disease burden, GDP per capita 2 has increased, and the global nutritional landscape has also changed (Figure 1A-B). Both socioeconomic status and nutritional factors, are emerging critical confounders for asthma1. However, so far, most studies have neglected to consider their correlations and interactions, including among nutrients within diets (Figure 1C-E). They instead focused on individual parameters alone, like specific diets or foods 3. Here, we adopted a recently published approach 2 to systematically interrogate the relationship between nutrient supply, a good proxy of food environment, socioeconomic status and asthma disease burden at a global scale over time. We focused on macronutrient supplies and their interactions, considering their important associations with many facets of health.Various multi-response generalized additive mixed models (GAMMs) were used to analyze the effects on asthma disease burden from macronutrient supplies and GDP over time (Supplementary Methods). In all analyses, a model considering the interactions of macronutrient supply and GDP, and an additive effect of time was favoured (Supplementary Table 1, 3). This suggested combinatory effects of macronutrients on asthma and the impacts of socioeconomic changes.The most recent year with all data available, 2018, is shown as a representative (Figure 1F-G, Supplementary Table 1-2). In brief, predicted association between asthma prevalence and macronutrient supplies were visualized using response surfaces on macronutrient supply plots. We focused on the fat (x -axis) and carbohydrate (y -axis) supplies while holding protein at 25%, 50% and 75% quantiles of global supply. Across the response surfaces, red indicated higher asthma disease burden, while blue indicated lower.In our modelling, carbohydrate supply was most strongly associated with increases of asthma prevalence rates, while fat supply had the opposite effects (Figure 1F). This is reflected by the purple isocaloric line, along which the total energy from macronutrients remained constant but increasing fat:carbohydrate ratio decreased the allergy prevalence. Protein supply conferred less influences. Similar patterns were found for asthma incidences (Figure 1G, Supplementary Table 3-4) independent of gender (Supplementary Figure 1-2) and were not confounded by the total macronutrient energy supply, as changing total energy while holding fat:carbohydrate ratio constant (red radial in figures) minimally impacted asthma disease burden.This represents the first study to link asthma to global food environment. Our results imply a driving role of carbohydrate supply for the asthma disease burden, after adjusting for the plausible interactions between macronutrients, total energy supply and socioeconomic status.Interestingly, previous studies found that ketogenic diets, low in carbohydrates, might ameliorate established asthma 4, supporting our findings that ketogenic-like food environments are associated with lower asthma disease burden. Although further in-depth investigations are needed, diet quality might be an intriguing explanation for the positive association between carbohydrate supply and asthma. For example, high- and ultra-processed foods low in fibre have been found to be related to asthma development 3,5, while we have previously shown that dietary fibre exhibited a strong immune regulatory influence, protecting against asthma6.Hence, future studies in more depth are warranted to investigate the associations between macronutrient supply and asthma, including also other related socioeconomic and environmental factors. Such studies will be critical for guidance to future clinical research and practice and public health interventions.Figure 1. Association of global macronutrient supply and asthma disease burden. A. Age-standardized asthma prevalence (blue) and incidence rate (red) of both sexes as functions of year. B.Global GDP per capita (in US dollars, black) and supplies of carbohydrate (green), protein (red) and fat (brown) as functions of year. C-E. Correlations among variables for global data from 1990-2018 (C ) and for different countries in 1990 (D ) and 2018 (E ). Correlation coefficients are shown. F-G.Predicted effects of macronutrient supply on age-standardized asthma prevalence rate (F ) and incidence rate (G ) of both sexes (See Supplementary Information for statistics and interpretation).

Artemisia annua sublingual immunotherapy in children with seasonal allergic rhinitis To the Editor,Artemisia pollen is the main aeroallergen of seasonal allergic rhinitis (SAR) in summer and autumn.1,2Artemisia annua Allergens Sublingual Immunotherapy (SLIT) Drops (Zhejiang Wolwo Bio-Pharmaceutical Co., Ltd., Zhejiang, China, National Drug Approval No.: S20210001) is the only standardized SLIT preparation approved in China for treatingArtemisia-induced allergic rhinitis with or without conjunctivitis (AC).3 In this study, we aimed to evaluate the safety and efficacy of A. annua- SLIT in children with SARs.Pediatric patients with at least a two-year clinical history ofArtemisia pollen-induced SAR with or without AC from Inner Mongolia were included in this randomized, double-blind, placebo-controlled, single-center clinical trial and randomized to receive A. annua -SLIT or placebo at a 2:1 ratio for approximately 28 weeks. The combined score of medication and rhinitis symptoms (CSMS; primary endpoint) and combined score of medication and rhinoconjunctivitis symptoms (CSMRS; secondary endpoint) were recorded to evaluate efficacy; adverse events (AEs) were reported to assess safety.Fifty-seven eligible patients aged 4–18 years were randomized into the SLIT (n=38) and placebo (n=19) groups (Figure 1). Finally, 54 patients (SLIT group: n=36; placebo group: n=18) completed the study with 3 patients withdrew by themselves. No significant differences were observed between the groups in terms of sex, age, atopic status, comorbidity of other allergic diseases, and CSMS and CSMRS scores in the previous pollen season (P >0.05, Table S1).The 2019 pollen season in Inner Mongolia was from 20th July to 7th September (50 days; Figure 2A). The temporal variation of daily CSMRS in both groups showed a similar trend of positive correlation with pollen concentration throughout the pollen season (SLIT group: r=0.66, 95% CI: 0.53–0.76; placebo group: r=0.68, 95% CI: 0.56–0.77). The SLIT group showed significant improvements in CSMS (1.55±0.81 vs. 1.97±0.73) and CSMRS (1.46±0.75 vs. 1.88±0.75) compared with the placebo group (P <0.05, Figure 2B–C). Fifty-three (98.1%) patients experienced AEs [35, SLIT group; 18, placebo group] (Table S2). All AEs were mild or moderate and resolved without any action or by adjusting the dose of the study drug. There were no significant differences in the incidence and severity of AEs between the groups (P >0.05). Epinephrine use was not reported, and no patients withdrew from the trial because of AEs. Furthermore, 94.4% and 100% of patients in the SLIT and placebo groups, respectively, experienced treatment-related AEs (TRAEs), which frequently occurred in the nose, eyes, throat, and tongue in both groups (P >0.05, Figure 2D). The common TRAEs in children with SLIT are shown in Figure 2E. Most TRAEs in the SLIT group were mild, similar to those in the placebo group.To our knowledge, this is the first study to report the efficacy and safety of A. annua -SLIT in a Chinese pediatric population. Our results showed a consistent trend of clinical efficacy improvements withA. annua -SLIT in children similar to those in adults.4 Recently, a cumulative AE incidence of 93.0% was reported with ragweed SLIT in children and adolescents, with no serious AEs.5 The incidence of AEs in our study were comparable to those in the previous study. Lou et al. found that the most common TRAEs in adults with A. annua -SLIT were mild or moderate.4,6 Our results showed a safety profile similar to that in adults. No new safety signals emerged, and no throat irritation was observed in adults.In conclusion, 28-week A. annua -SLIT treatment was effective and safe for children with SAR, with no major safety concerns. Investigating the benefits of A. annua -SLIT in children will not only expand its application for treatment but also provide the basis for intervention in the early phase of SAR.

Correspondence to “Association between Chronic Rhinosinusitis and New Onset Asthma Implications for Prevention”To the Editor,We have attentively reviewed the article by Schwartz et al. titled ’Sinus inflammation and chronic rhinosinusitis are associated with a diagnosis of new onset asthma in the following year’1. This study significantly advances our understanding of the relationship between chronic rhinosinusitis (CRS) and the onset of new asthma diagnoses. However, we would like to offer some suggestions.First and foremost, it is important to consider potential confounders that might influence the observed association between CRS and the development of asthma. Factors such as environmental exposures or socio-economic status could potentially impact this relationship.2,3Secondly, this study focuses on the CRS-asthma association but doesn’t probe how CRS treatments affect asthma outcomes. Phillips et al4showed timely CRS treatments, such as functional endoscopic sinus surgery (FESS) might lower asthma risks. Addressing eosinophilic inflammation and related conditions, e.g. depression, could also influence asthma results5,6. Understanding CRS treatment impacts on asthma is crucial for patient care, necessitating more research to inform clinical guidance.Furthermore, it’s important to consider that this study might have overestimated the connection between chronic rhinosinusitis (CRS) and asthma due to certain methodological limitations. The study did not take into account the 12-week duration requirement for CRS, potentially leading to an overrepresentation of cases and an overestimation of the associations . Additionally, the reliance on electronic health records (EHR) for identifying disease outcomes introduces the possibility of measurement errors or biases, which could further contribute to the overestimation of the observed associations . Therefore, it is crucial for future research endeavors to refine their methods and address these limitations in order to obtain a more accurate understanding of the strength of the CRS-asthma association.In conclusion, this study by Schwartz et al.’s research highlights a link between CRS and new asthma cases, but further exploration is needed on potential confounders, the effect of CRS treatments, and potential overestimations.1. Schwartz BS, Pollak JS, Bandeen-Roche K, et al. Sinus inflammation and chronic rhinosinusitis are associated with a diagnosis of new onset asthma in the following year. Allergy . Oct 2023;78(10):2659-2668. doi:10.1111/all.157712. Celebi Sozener Z, Cevhertas L, Nadeau K, Akdis M, Akdis CA. Environmental factors in epithelial barrier dysfunction. J Allergy Clin Immunol . Jun 2020;145(6):1517-1528. doi:10.1016/j.jaci.2020.04.0243. Velasquez N, Gardiner L, Cheng TZ, et al. Relationship between socioeconomic status, exposure to airborne pollutants, and chronic rhinosinusitis disease severity. Int Forum Allergy Rhinol . Feb 2022;12(2):172-180. doi:10.1002/alr.228844. Phillips KM, Bergmark RW, Hoehle LP, Caradonna DS, Gray ST, Sedaghat AR. Chronic rhinosinusitis exacerbations are differentially associated with lost productivity based on asthma status. Rhinology . Dec 1 2018;56(4):323-329. doi:10.4193/Rhin18.0335. Shah SA, Kobayashi M. Pathogenesis of chronic rhinosinusitis with nasal polyp and a prominent T2 endotype. Heliyon . Sep 2023;9(9):e19249. doi:10.1016/j.heliyon.2023.e192496. Brunner WM, Schreiner PJ, Sood A, Jacobs DR, Jr. Depression and risk of incident asthma in adults. The CARDIA study. Am J Respir Crit Care Med . May 1 2014;189(9):1044-51. doi:10.1164/rccm.201307-1349OCAuthorIressa Cheng 1, Chin-Yuan Yii MD2,3. Su-Boon Yong4,5,Liang-Chun Shih MD, PhD 4,61 School of Medicine, Chung Shan Medical University, Taichung, Taiwan.2 Division of Gastroenterology and Hepatology, Department of Internal Medicine, Landseed International Hospital, Taoyuan, Taiwan;3 Department of Biomedical Sciences and Engineering, National Central University, Taoyuan, Taiwan.4 Department of Medicine, College of Medicine, China Medical University, Taichung, Taiwan.5 Department of Allergy and Immunology, China Medical University Children’s Hospital, Taichung, Taiwan.6 Department of Otorhinolaryngology-Head and Neck SurgeryAuthor Contributions:Iressa Cheng: Conceptualization, Writing - Original Draft PreparationChin-Yuan Yii: Conceptualization, Writing - Review & EditingLiang-Chun Shih: Writing - Review & EditingJiu Yao Wang: Conceptualization, Writing - Review & Editing, SupervisionSu-Boon Yong: Conceptualization, Writing - Review & Editing, Supervision, Project Administrationconflict of interests :The authors declare no conflict of interest.Corresponding author:1.Su-Boon Yong MD, PhD.Department of Medicine, College of Medicine, China Medical University, Taichung, Taiwan.Department of Allergy and Immunology, China Medical University Children’s Hospital, Taichung, [email protected]. Jiu Yao Wang MD, PhDCenter for Allergy, Immunology, and Microbiome (A.I.M.), China Medical University Hospital, Taichung, Taiwan, China.Department of Allergy, Immunology, and Rheumatology (AIR), China Medical University Children’s Hospital, Taichung, Taiwan, [email protected]

Proton pump inhibitors (PPIs) are invaluable therapeutic options in a variety of dyspeptic diseases. In addition to their well-known risk profile, PPI consumption is related to food and environmental allergies, dysbiosis, osteoporosis, as well as immediate and delayed hypersensitivity reactions (HSRs). The latter, although a rare event, around 1-3%, due to the extraordinarily high rate of prescription and consumption of PPIs are related to a substantial risk. In this Position Paper, we provide clinicians with practical evidence-based recommendations for the diagnosis and management of HSRs to PPIs. Furthermore, the unmet needs proposed in the document aim to stimulate more in-depth investigations in the topic.

Telehealth is an emerging approach that uses technology to provide healthcare remotely. Recent publications have outlined the importance of supporting the transition to self-management of adolescents with allergic conditions. However, no synthesis of the evidence base on the use and impact of telehealth interventions for this purpose has been conducted to date. This review achieves these aims, in addition to exploring the language use surrounding these interventions, and their implementation. Four databases were searched systematically. References were independently screened by two reviewers. Methodological quality was assessed using the Mixed Methods Appraisal Tool. A narrative synthesis was undertaken. Eighteen papers were included, reporting on fifteen telehealth interventions. 86% targeted adolescents with asthma. Mobile applications were the most common telehealth modality used, followed by video-conferencing, web-based, virtual reality and artificial intelligence Five intervention content categories were identified; educational, monitoring, behavioural, psychosocial and healthcare navigational. Peer and/or healthcare professional interaction, gamification and tailoring may increase engagement. The studies showed positive effects of the interventions or no difference from active controls, in self-management outcomes such as knowledge, health outcomes such as quality-of-life, and economic outcomes such as healthcare utilisation. The most common implementation outcomes reported were acceptability, appropriateness, feasibility and fidelity.

Background Drug hypersensitivity reactions (DHRs) to platinum-based drugs are heterogenous and restrict their access, and drug desensitization (DD) has provided a ground-breaking procedure for their re-introduction, although the response is heterogeneous. We aimed to identify the phenotypes, endotypes and biomarkers of reactions to carboplatin and oxaliplatin and their response to DD. Methods Seventy-nine patients presenting with DHRs to oxaliplatin (N=46), and carboplatin (N=33) were evaluated at the Allergy Departments of two tertiary care hospitals in Spain. Patient symptoms, skin testing, biomarkers, and outcomes of 267 DDs were retrospectively analyzed. Results Oxaliplatin-reactive patients presented with type I (74%), cytokine release reaction (CRR) (11%), and mixed (Mx) (15%) phenotypes. In contrast, carboplatin reactive patients presented with predominantly type I (85%) and Mx (15%) but no CRRs. Out of 267 DDs, breakthrough reactions (BTRs) to oxaliplatin occurred twice as frequently as carboplatin (32% versus 15%; p<0.05). Phenotype switching from type I to another phenotype was observed in 46% of oxaliplatin DDs compared to 21% of carboplatin DDs. Tryptase was elevated in type I and Mx reactions, and IL-6 in CRR and Mx, indicating different mechanisms and endotypes. Conclusion Carboplatin and oxaliplatin induced three different types of reactions with defined phenotypes and endotypes amendable to DD. Although most of the initial reactions for both were type I, oxaliplatin presented with unique CRR reactions. During DD, carboplatin reactive patients presented mostly type I BTR, while oxaliplatin reactive patients frequently switched from type I to CRR, providing a critical difference and the need for personalized DD protocols.

Background: Increasing evidence are available about the presence of increased serum concentration of Immunoglobulin (Ig) Free Light Chains (FLCs) in both atopic and non-atopic inflammatory diseases, including severe asthma, providing a possible new biomarker of disease, disease severity and also an alternative approach to the treatment. Methods: We analyzed clinical and laboratory data, including FLCs, obtained from a cohort of 79 asthmatic subjects, clinically classified into different GINA steps. A control group of 40 age-matched healthy donors (HD) was considered. Particularly, HD have been selected according to the absence of monoclonal components (in order to exclude paraproteinemias), were tested for total IgE (that were in the normal ranges) and were negative for aeroallergens specific IgE. Moreover, no abnormality of common inflammatory markers (i.e. erythrocyte sedimentation rate, C-reactive protein) was detectable. Results: FLC-k levels were significantly increased in the asthmatic population, compared to the control group. Despite the absence of statistically significant differences in FLC-λ levels, the FLC-k/FLC-λ ratio displayed remarkable differences between the two groups. A positive correlation between FLC-κ and FLC-λ levels was found. FLC- λ level displayed a significant negative correlation with the FEV1 value. Moreover, the FLC-κ /FLC- λ ratio was negatively correlated with the SNOT-22 score and a positive correlation was observed between FLCs and Staphylococcus Aureus IgE enterotoxins sensitization. Conclusions: Our findings confirmed the role of FLCs in asthma as a potential biomarker in an inflammatory disease characterized by different endotypes and phenotypes. In particular, FLC-κ and FLC-k/FLC-λ ratio could be a qualitative indicator for asthma, while FLC-λ levels could be a quantitative indicator for disease severity.

Abstract: Background: The European Academy of Allergy and Clinical Immunology’s (EAACI) is updating the Guidelines on Food Allergy Diagnosis. We aimed to undertake a systematic review of the literature with meta-analyses to assess the accuracy of diagnostic tests for IgE-mediated food allergy. Methods: We searched three databases (Cochrane CENTRAL (Trials), MEDLINE (OVID) and Embase (OVID)) for diagnostic test accuracy studies published between 1 st October 2012 and 30 th June 2021 according to a previously published protocol (CRD42021259186). We independently screened abstracts, extracted data from full-texts, and assessed risk of bias with QUADRAS 2 tool in duplicate. Meta analyses were undertaken for food-test combination where 3 or more studies were available. Results: 149 studies comprising 24,489 patients met the inclusion criteria and were generally heterogeneous. 60.4% of studies were in children ≤12 years of age, 54.3% undertaken in Europe, ≥95% conducted in a specialized pediatric or allergy clinical setting and all included oral food challenge in at least a percentage of enrolled patients, in 21.5% DBPCFC. Skin prick test (SPT) with fresh cow’s milk and raw egg had high sensitivity (90% and 94%) for milk and cooked egg allergies. Specific IgE to individual components had high specificity: Ara h 2 had 92%, Cor a 14 95%, Ana o 3 94%, casein 93%, ovomucoid 92/91% for the diagnosis of peanut, hazelnut, cashew, cow’s milk and raw/cooked egg allergies, respectively. BAT was highly specific for the diagnosis of peanut (90%) and sesame (93%) allergies. Conclusions: SPT and specific IgE to extracts had high sensitivity whereas specific IgE to components and BAT had high specificity to support the diagnosis of individual food allergies. PROSPERO registration: CRD42021259186 Funding: European Academy of Allergy (EAACI).

A document by Qing-Ling Fu. Click on the document to view its contents.

Background Allergic rhinitis (AR) is one of the most common chronic diseases worldwide. There are limited prospective long-term data regarding persistency and remission of AR. The objective of this study was to investigate the natural course of pollen-induced AR (pollen-AR) over 20 years, from childhood into early adulthood. Methods Data from 1137 subjects in the Barn/Children Allergi/Allergy Milieu Stockholm Epidemiologic birth cohort (BAMSE) with a completed questionnaire regarding symptoms, asthma, treatment with allergen immunotherapy (AIT) and results of allergen-specific IgE for inhalant allergens at 4, 8, 16 and 24 years were analysed. Pollen-AR was defined as sneezing, runny, itchy, or blocked nose; and itchy or watery eyes when exposed to birch and/or grass pollen in combination with allergen-specific IgE ≥0.35kU A/l to birch and/or grass. Results Approximately 75% of children with pollen-AR at 4 or 8 years had persistent disease up to 24 years, and 30% developed asthma. The probability of persistency was high already at low levels of pollen-specific IgE. The highest rate of remission from pollen-AR was seen between 16 and 24 years (21.5%), however the majority remained sensitized. This period was also when pollen-specific IgE-levels stopped increasing and the average estimated annual incidence of pollen-AR decreased from 1.5% to 0.8% per year. Conclusion Children with pollen-AR are at high risk of persistent disease for at least 20 years. Childhood up to adolescence seems to be the most dynamic period of AR progression. Our findings underline the close cross-sectional and longitudinal relationship between sensitization, AR, and asthma.

Background: Food-induced immediate response of the esophagus (FIRE) is a new phenomenon that has been described in eosinophilic esophagitis (EoE) patients. It is suspected when unpleasant symptoms occur suddenly on contact of the triggering food with the esophageal surface and recur with repeated exposures. It can often be mistaken for pollen-food allergy syndrome (PFAS) and solid food dysphagia. Data on FIRE is limited to one survey study and case reports, and there are no screening studies conducted on either adults or children with EoE. In this study, we aimed to screen children aged ≥7 years old with EoE for FIRE. Methods: Demographic data were collected from medical records. A questionnaire about FIRE was applied to all participants. Skin prick tests (SPTs) were done on suspected patients to identify the triggering foods. FIRE is defined as suitable clinical symptoms with suspected food allergen exposure. Results: Seventy-eight patients (74.4% male, median age: 13.5 years) were included. Unpleasant and recurrent symptoms distinct from dysphagia with specific foods were reported in %16.7 of the patients, all of whom had concomitant allergic rhinitis (AR). The symptoms described by almost all patients were oropharyngeal itching and tingling (PFAS: 15.3%) excluding only one patient reporting retrosternal narrowing and pressure after specific food consumption (FIRE: 1.2%). Conclusions: Although definitive conclusions regarding the true prevalence of FIRE cannot be made, it does not seem to be common as PFAS. However, it deserves questioning particularly in the presence of concurrent AR and/or PFAS in children with EoE.

Tropical urban environments reveal a strong association of CD45RBloCD161+ Th2 subset to allergic rhinitis To the Editor:Allergic airway diseases such as allergic rhinitis (AR) affects more than 400 million individuals worldwide and afflicts substantial health and economic morbidity. [1] AR is strongly associated with a type 2 response, characterized by the cytokines IL-5, IL-4 and IL-13. However, the key drivers behind AR immunopathogenesis remained to be elucidated. This study aims to identify critical pathogenic cell populations associated with AR using the Singapore System Immunology Cohort (SSIC) [2] and a clinician-diagnosed paediatric cohort with active AR manifestation (Supplementary Table 1 ). In both cohorts, the eosinophilic nature of AR was confirmed by higher blood eosinophil numbers (Supplementary Figure 1 ).Whole blood gene expression analysis revealed a total of 23 probes representing 20 unique genes were associated with AR in the SSIC (Table 1A ). To account for ethnicity and environmental influences we validated our findings in BAMSE population-based cohort comprising of Swedish adolescents. Table 1B shows 11 DEGs which was also associated with AR, confirming the transferability of our findings to other populations. For the top DEGs that reached nominal significance in the SSIC we performed an Ingenuity Pathway Analysis (IPA). Supplementary Table 2 revealed important pathways related to hypersensitivity and inflammation and also functional enrichment for eosinophils, basophils and mast cells. In particular, functional activation of Th2 was highlighted as a key pathway for AR pathogenesis. As CRTH2 was reported to be expressed by cell types involved in the eosinophilic response, [3] an unsupervised cluster analysis was performed on the CRTH2+ subset in PBMC of individuals from SSIC (Figure 1 A and B ) to determine CRTH2+ subsets associated with AR. We found that CD161+Th2 subsets in particularly to be strongly associated with AR (Figure 1C and D ) (Supplementary Figure 2 ). Further characterization found that the marker CD45RB to be significantly downregulated on CD161+Th2 cells of AR individuals (Figure 1E ). Low CD45RB expression on T cells is indicative of a mature phenotype. Interestingly, significantly higher circulatory plasma IL-5 levels (Figure 1F) . Furthermore we could also demonstrate AR individuals produced significantly higher IL-5 in an in vitro PMA-stimulation assay (Figure 1G ).While we noted a small population of IL-5 secreting conventional CD161-Th2 (cTh2), IL-5 secretion was significantly elevated in CD161+Th2 cells (Figure 1H ). Strikingly, IL-5 was found to be predominantly secreted by CD45RBlo subset in both cTh2 and CD161+Th2 (Figure 1H and I ). There was also a significant increase in the IL-5 producing CD45RBloCD161+Th2 population from the AR individuals (Figure 1I ). These findings confirm CD45RBloCD161+Th2 as the main producers of IL-5.We further validated our findings in a second paediatric cohort with clinically diagnosed active AR manifestations. To further refine CD161+Th2 subset that is associated with AR, we performed unsupervised PhenoGraph and UMAP clustering on CD161+Th2 (Supplementary Figure 3A and B ). Amongst the UMAP clusters, “cluster 3” was found to be significantly associated with active AR (Supplementary Figure 3C and D ). Deep characterization reveals “cluster 3” to be an IL-5 secreting CD45RBlopopulation, confirming our earlier observation (Supplementary Figure 3E ). Furthermore, this cluster appeared to be a highly differentiated population of mature CD161+Th2 cells with an activated phenotype secreting IL-2, IL-3, IL-4, IL-9 and IL-13 concomitantly (Supplementary Figure 3E and F ). Thus, the severity of eosinophilic airway allergies such as AR seems to be driven by an activated terminally differentiated CD161+Th2 subset that is able to secrete a complex set of inflammatory cytokines.The presence of CD45RBloCD161+Th2 population in both cohorts shows the persistence and pertinence of this population in the pathogenesis of AR. Both cohorts described in this study were collected in Singapore, whereby majority of the individuals are sensitized against HDM. HDM is a perennial allergen in tropical nations such as Singapore, thus T cells in atopic individuals undergo constant stimulation. This could explain the strong association observed between CD45RB expression on CD161+Th2 cells and atopy markers despite the fact that not all subjects demonstrated active AR symptoms during the collection of SSIC cohort. Taken together, our current study unifies the markers previously reported for allergic-specific Th2 subsets and provides clarity for the pathogenic Th2 subset previously reported in different allergic diseases.[4-6] Neutralizing the CD45RBloCD161+Th2 subset should disrupt the allergic response pathway, thus providing a target for lasting therapeutic interventions. Moreover, these cells may also be leveraged as a biomarker for the effectiveness of immunotherapy as well as a potential biomarker of public health surveillance of allergic individuals.

Transcription therapy is an emerging approach that centers on identifying the factors associated with the malfunctioning gene transcription machinery that causes diseases and controlling them with designer agents. Until now, small molecule drugs targeting the epigenetic enzymes and critical signaling pathways have been the primary research focus in therapeutic gene modulation. However, nucleic acid-based small molecules have gained popularity in recent years as they could be pre-designed on demand to achieve operative control over the dynamic transcription machinery that governs how the immune system responds to diseases. Pyrrole-imidazole polyamides (PIPs) are well-established DNA-based small molecule gene regulators that overcome the limitations of their conventional counterparts owing to their sequence-targeted specificity, versatile regulatory efficiency and biocompatibility. Here, we emphasize the rational design of PIPs, their functional mechanism and their potential as targeted transcription therapeutics for diseases by regulating the immune response. Furthermore, we also discuss the challenges and foresight of this approach in personalized immunotherapy in precision medicine.

Gut microbiota andLactobacillus species maintain the small intestine stem cell niche and ameliorate the severity of necrotizing enterocolitis Svabova Tereza1*, Jelinkova Anna1, Gautam Umesh Kumar11Laboratory of Gnotobiology, Institute of Microbiology of the Czech Academy of Sciences, 54922 Novy Hradek, Czech Republic.*corresponding author: [email protected] microbiota plays an undisputed role in mammalian development and physiology. It enhances energy extraction from ingested food, protects against harmful pathogens, regulates immune function, and strengthens biochemical signaling. In mammals, including humans, colonization of the gut by microbes begins at birth1, and several recent studies have shown that the microbiome contributes to postnatal host development in early childhood. In this sense, microbial dysbiosis in infancy has been associated with certain diseases such as inflammatory bowel disease, cardiometabolic disorders, cancer, and neuropsychiatric disorders2.The intestinal epithelial cells are in direct contact with a large number of bacteria and the external environment, forming a barrier between inside and outside while fulfilling a critical role in the absorption of nutrients. The small intestine crypt-villus architecture is a unique structure that provides a microenvironment in which intestinal stem cells (ISCs) differentiate into a variety of different epithelial subtypes. These subtypes include enterocytes, also known as intestinal epithelial cells (IECs), Paneth cells, goblet cells, enteroendocrine cells, tuft cells, and microfold cells (M cells)3.Kim et al. demonstrated that early life gut microbiota exposure promotes the differentiation of intestinal stem cells into Paneth cells by regulating numbers of CD206+macrophages associated with epithelial Wnt signaling, which maintains mesenchymal niche cell proliferation (Figure 1). They suggested that the maintenance of this stem cell niche is critical for small intestinal homeostasis and its disruption (e.g., by antibiotic administration) can lead to inflammatory conditions, which can manifest as necrotizing enterocolitis (NEC). NEC is a severe inflammatory disease affecting the small intestine, especially in preterm infants, and is the leading cause of death in this group.To investigate the role of the microbiota and intestinal stem cell differentiation in the pathogenesis of NEC, Kim et al. induced NEC-like phenotypes in neonatal mice by exposing them to hypoxia and gavage feeding of hyperosmolar formula and LPS. ATB-induced dysbiosis resulted in further impaired stem cell niche in the small intestine and led to severe NEC manifestation. They also confirmed previous findings that microbial dysbiosis in NEC is associated with an increased abundance ofProteobacteria and a concomitant underrepresentation ofFirmicutes and Lactobacillus 4. To determine whether members of genus Lactobacillus affect Paneth cell formation during NEC onset, Kim et al. treated pregnant females and their pups with selected Lacticaseibacillus rhamnosus (Lr) strain in the presence or absence of NEC experimental conditions. They found that Lr transplantation corrected the impaired development of the mesenchymal niche and Paneth cell differentiation and consequently partially rescued the NEC-like phenotypes (Figure 1)4.Previous studies in germ-free mice and mice with Toll-like receptor knockout have highlighted the key relationship between the microbiome and NEC development5. Probiotic administration has been suggested as a potential strategy to prevent NEC. In general, probiotic bacteria, including Lactobacillus species, modulate microbiota composition, intestinal epithelial barrier function, and cytokine secretion. Kim et al. showed that transplantation of Lr restored the amount of Lactobacilli resulting in an improvement of NEC-like phenotypes. We have recently shown that administration ofLactiplantibacillus plantarum WJL also increased the proliferation of intestinal epithelial stem cells in chronically undernourished juvenile mice, resulting in improved growth of the young. This effect was strictly bacterial strain-dependent, and NOD2 signaling in intestinal epithelial cells was essential for the bacteria-mediated beneficial effect6. A growing body of evidence suggests that the strain specificity of probiotic microbes and their efficacy in alleviating specific diseases are crucial aspects that are often overlooked when selecting the best probiotic microbes7. Therefore, it would be important to determine whether all probiotic bacterial species or even different Lr strains promote the stem cell niche development by the same mechanism. Further, as it has been shown that NOD2 signaling plays a crucial role in epithelial stem cell proliferation, the role of this receptor in the NEC prevention and development should be probed.To sum up, the study by Kim et al. provides another important contribution to the understanding of the mechanism of NEC pathogenesis. However, more research is needed to fully understand the role ofLactobacilli and other probiotic bacteria in the prevention of NEC and to strengthen their potential as therapeutic agents to combat this serious disease.

Sequential proteomic profiling of patients with Stevens Johnson-Syndrome or Toxic Epidermal NecrolysisEmmanuel Contassot (PhD) 1, 2, Brüggen Marie-Charlotte (MD, PhD) 3, 4, 51 Dermatology Department, University Hospital of Basel, Basel, Switzerland2 Department of Biomedicine, University of Basel, Basel, Switzerland3 Department of Dermatology, University Hospital Zurich, Zurich, Switzerland4 Christine Kühne Center for Allergy Research and Education CK-CARE, Davos, Switzerland5 Faculty of Medicine, University of Zurich, Zurich, Switzerland

IL-17 has emerged as an important cytokine in protecting the host from mucosal infections, but also as a pathogenic determinant and therapeutic target in numerous autoimmune and inflammatory diseases (e.g. psoriasis, psoriatic arthritis and ankylosing spondylitis, inflammatory bowel disease and multiple sclerosis) [(1)](#ref-0001). The IL-17 family includes six members (IL-17A to IL-17F) that act through the IL-17 receptors [(1)](#ref-0001). The most studied IL-17A, as well as IL-17F, binds to IL-17RA and IL-17RC resulting in heterodimerization. Currently IL-17A, IL-17F, IL-17RA or IL-23, a cytokine produced by innate immune cells that promotes expansion of Th17 cell populations, are targetable by monoclonal antibodies (mAbs). These mAbs have been approved for the treatment of different autoimmune diseases, most notably psoriasis, where their efficacy has outperformed conventional non-steroidal anti-inflammatory and tumor necrosis factor (TNF) blocking drugs. However, clinical trials and real-life experience have shown an increase in fungal and bacterial upper respiratory tract infections in patients treated with mAbs that block IL-23/IL-17 signaling. Accordingly, single nucleotide polymorphisms in genes encoding IL-17A, IL-17RA, IL-17RC, IL-23, or NF-κB activator 1 (ACT1, an adapter protein downstream of the IL-17R) which abrogate cellular responsiveness to IL-17A, were associated with susceptibility to chronic mucocutaneous candidiasis (CMC), a persistent infection of the skin, nails, and/or mucous membranes with commensal Candida species [(2)](#ref-0002). So new effective targeted approaches in IL-17 signaling are desirable. Knizkova and colleagues identified a new adaptor molecule involved in the IL-17/IL-17R cascade [(3)](#ref-0003). Through murine and human cell models, the authors found that CMTM4 (CKLF Like MARVEL Transmembrane Domain Containing 4) constitutively bound to the subunit IL-17RC becoming integral part of the IL-17R signaling complex (IL-17RSC) upon IL-17A stimulation. CMTM4 promoted the surface expression of IL-17RC by regulating posttranslational modifications, especially IL-17RC glycosylation and trafficking to trans-Golgi up to plasma membrane. CMTM4 was required for the recruitment of adapter ACT1, for the activation of p38, JNK and transcription of genes encoding proinflammatory cytokines upon IL-17A stimulation (Figure 1A). Keratinocytes from the tail of Cmtm4−/− mice specifically express lower levels of IL-17RC respect to Cmtm4+/+ mice (Figure 1B). In vivo, when imiquimod (IMQ) was applied on the ears or shaven backs of Cmtm4−/− mice, they developed less severe psoriatic lesions and lower local expression of IL-17A target genes compared to Cmtm4+/+ mice (Figure 1C).

Background: Respiratory birch pollen allergy and associated oral allergy syndrome affect more than 150 million people. IgE cross-sensitization to major birch pollen allergen Bet v 1 and pathogenesis-related (PR10) plant food allergens is responsible for the pollen-food allergy syndrome. Methods: We designed a recombinant protein, AB-PreS, consisting of non-allergenic peptides derived from the IgE binding sites of Bet v 1 and the cross-reactive apple allergen, Mal d 1, fused to the PreS domain of HBV surface protein as immunological carrier. AB-PreS was expressed in E. coli and purified by chromatography. The allergenic activity of AB-PreS was tested using sera and basophils from birch pollen patients allergic. The protective effect of AB-PreS was assessed by inhibition ELISA test using sera allergic patients and from immunized rabbits. Results: IgE-binding experiments and basophil activation test revealed the hypoallergenic nature of AB-PreS. IgG antibodies induced by 5 injections with AB-PreS inhibited allergic patients’ IgE binding to Bet v 1 and Mal d 1 better than did IgG induced by up to 30 injections of six licensed birch pollen allergen extract-based vaccines. Additionally, immunization with AB-PreS induced HBV-specific antibodies potentially protecting the infection. Conclusion: The recombinant AB-PreS-based vaccine is hypoallergenic, safe and superior to currently registered allergen extract-based vaccines for the treatment of the birch pollen food allergy syndrome.

The field of medicine is witnessing an exponential growth of interest in Artificial Intelligence (AI), which enables new research questions and the analysis of larger and new types of data. Nevertheless, applications that go beyond proof of concepts and deliver clinical value remain rare, especially in the field of allergy and immunology. This narrative review provides a fundamental understanding of the core concepts of AI and critically discusses its limitations and open challenges, such as data availability and bias, along with potential directions to surmount them. We provide a conceptual framework to structure AI applications within this field and discuss forefront case examples. Most of these applications of AI and machine learning in allergy concern supervised learning and unsupervised clustering, with a strong emphasis on diagnosis and subtyping. A perspective is shared on guidelines for good AI practice to guide readers in applying it effectively and safely, along with prospects of field advancement and initiatives to increase clinical impact. We anticipate that AI can further deepen our knowledge of disease mechanisms and contribute to precision medicine in allergy.