ALLERGY 的目的是推进、影响和交流过敏/免疫学学科的各个方面，包括教育、基础、转化和临床研究，并保持基础和临床过敏/免疫学之间的联系。ALLERGY 是一本国际期刊，其贡献者和读者来自所有国家。 ALLERGY 发表原创文章、评论、立场文件、指南、社论、新闻和评论、致编辑的信函和通信。文章的接受纯粹是基于科学价值和质量。

The purpose of Allergy: European Journal of Allergy and Clinical Immunology is to advance, influence, and communicate all aspects of the field of allergy and immunology, including education, basic research, translational research, and clinical studies, while maintaining a close connection between basic and clinical allergy/immunology. This is an international journal with contributors and readers from all countries. Allergy publishes original research articles, reviews, position papers, guidelines, editorials, news, letters to the editor, and communications. Acceptance of articles is solely based on their scientific value and quality.

《Allergy: European Journal of Allergy and Clinical Immunology》旨在推动、影响和交流过敏与免疫学领域的各个方面，包括教育、基础研究、转化研究和临床研究，并保持基础与临床过敏/免疫学之间的紧密联系。该期刊是一本国际性期刊，贡献者和读者来自世界各地。《Allergy》发表原创研究文章、评论、立场文件、指南、社论、新闻、读者来信及其他通讯。文章的接受完全基于其科学价值和质量。

Allergy: European Journal of Allergy and Clinical Immunology

Abstract Background Asthma‐like symptoms in young children are orchestrated by the local airway immune response, but current knowledge largely relies on in vitro airway models. Azithromycin has been shown to reduce the duration of episodes with asthma‐like symptoms, but efficacy may depend on the individual child's immune response. Objectives To investigate in vivo upper airway immune mediator levels during episodes with asthma‐like symptoms in young children and their ability to predict the clinical response to azithromycin treatment. Methods A total of 535 children aged 0‐3 years from the Copenhagen Prospective Studies of Asthma in Childhood‐2010 mother‐child cohort were examined for immune mediator levels in samples of nasal epithelial lining fluid during episodes with asthma‐like symptoms as well as in the asymptomatic state. In a sub‐study, children with recurrent asthma‐like symptoms were randomized to either a 3‐day course of oral azithromycin (10 mg/kg; n = 32) or placebo (n = 38). In the current study, we compared the pretreatment immune mediator levels with the clinical response to treatment with azithromycin in an exploratory post hoc analysis. Results The immune mediator concentrations during vs outside episodes were significantly upregulated for IFN‐ɣ (ratio 1.73), TNF‐α (ratio 2.05), IL‐1β (ratio 1.45), IL‐10 (ratio 1.97), while CCL22 (ratio 0.65) was downregulated. Low levels of TNF‐α and IL‐10 and high levels of CCL22 predicted better treatment response to azithromycin ( P ‐values &lt; .05). Conclusion Upper airway immune mediator levels were altered during episodes of asthma‐like symptoms, and levels of TNF‐α, CCL22, and IL‐10 may predict the response to azithromycin treatment.

Christian J. Carlsson

Morten A. Rasmussen

Susanne B. Pedersen

Ni Wang

Jakob Stokholm

Bo L. Chawes

Klaus Bønnelykke

Hans Bisgaard

Allergy

Airway immune mediator levels during asthma‐like symptoms in young children and their possible role in response to azithromycin

The identification of sputum eosinophilia indicating corticosteroid responsiveness in subjects with severe asthma heralded the beginning of phenotyping asthmatic subjects based on airways inflammation. Since then, the heterogeneity of severe asthma has been explored and the importance of immunobiology has come sharply into focus with the identification of the key type‐2 cytokine pathways driving eosinophilic inflammation. The development of molecules targeting these type‐2 pathways has transformed severe asthma treatment, but necessitates robust clinical evaluation, biomarker profiling and assessment of comorbid factors to identify subjects most likely to benefit from these therapies. It has also become clear that targeting these pathways does not eradicate asthma symptoms and exacerbation risk; further work is needed to clarify underlying non‐type‐2 mechanisms in severe asthma pathways and possible therapeutic targets. This review addresses progress to date in clinical assessment and management of severe asthma and some of the challenges and unmet needs in severe asthma to achieve the goal of delivering individualized patient care.

P. Jane McDowell

Liam G. Heaney

Different endotypes and phenotypes drive the heterogeneity in severe asthma

不同内型和表型驱动重症哮喘的异质性

Abstract Background Eosinophils are key therapeutic targets in severe asthma that are suppressed by IL5 (mepolizumab) and IL5 receptor (benralizumab) blockade. The effect of IL5 pathway biologics on recently described homeostatic (hEOs) and inflammatory (iEOs) eosinophil subsets is unknown. We aimed to determine the relative impact of mepolizumab and benralizumab treatment on eosinophil subset and phenotype, and explore clinical associations of eosinophil subsets with severe asthma characteristics and treatment response. Methods We performed a cross‐sectional observational study of severe asthma (eosinophilic n = 32, non‐eosinophilic n = 23, mepolizumab‐treated n = 25), with longitudinal follow‐up of 30 eosinophilic participants at two timepoints (4–24 weeks, &gt;24 weeks) post‐commencement of mepolizumab ( n = 20) or benralizumab ( n = 10). Blood hEOs and iEOs were measured by flow cytometry assessment of surface CD62L protein. Results iEO proportion was significantly lower in mepolizumab‐treated participants in both the cross‐sectional and longitudinal study. Mepolizumab and benralizumab depleted iEOs to a similar extent, however a significantly greater number of hEOs remained in mepolizumab participants at follow‐up. Greater iEO proportion correlated with poorer asthma control in eosinophilic but not non‐eosinophilic asthma. Higher residual iEO proportion correlated with poorer asthma control in mepolizumab‐treated individuals. Reduced blood eosinophil viability was observed in around half of mepolizumab‐treated participants, which was associated with significantly better asthma control and spirometry. Conclusions Mepolizumab depletes iEOs and reduces circulating eosinophil viability in severe asthma but preserves a residual population of circulatory hEOs. In contrast benralizumab depleted both iEOs and hEOs. Higher iEO abundance and eosinophil viability are associated with poorer clinical outcomes following mepolizumab‐treatment. Monitoring circulating eosinophil phenotype and viability may be useful to predict biologic treatment response in severe asthma.

Michael Fricker

John Harrington

Sarah A. Hiles

Peter G. Gibson

Mepolizumab depletes inflammatory but preserves homeostatic eosinophils in severe asthma

美泊利单抗在重度哮喘中消耗炎症性但保留稳态嗜酸性粒细胞

Chronic rhinosinusitis with nasal polyposis (CRSNP) and asthma are inflammatory lesions of the respiratory epithelium. This study was conducted to evaluate predictive factors of bronchial hyperresponsiveness (BHR) in patients with CRSNP.BHR was evaluated using a methacholine bronchoprovocation test (MBPT) in 122 consecutive patients newly diagnosed with CRSNP at Seoul National University Hospital from January 2004 to June 2006. The following parameters were analyzed and compared between the BHR and non-BHR groups: symptoms, atopic status, current smoking, disease severity of CRSNP based on the Lund-Mackay scoring system of sinus CT, and counts of eosinophils in the serum and nasal tissues.Thirty-five percent of the patients were found to have BHR, and BHR was found to occur more frequently in patients that were currently suffering from sneezing (P = 0.007). In addition, the mean eosinophil counts of the serum and nasal tissues were higher in the BHR group than in the non-BHR group (P = 0.001 for the serum, P = 0.045 for the nasal tissues), and the eosinophil counts of the serum correlated to those of the nasal tissues (r = 0.334, P = 0.013). The disease severity, as determined by the Lund-Mackay scoring system, was not different between the two groups (P > 0.05). The best cutoff serum eosinophil count for predicting BHR in CRSNP patients was determined to be 300 cells/microl (sensitivity 70%, specificity 70%).Taken together, these results indicate that moderate to severe sneezing and a serum eosinophil count > or = 300 cells/microl may be predictive factors for BHR in patients with CRSNP.

D. H. Han

S. W. Kim

S. H. Cho

D. Y. Kim

C. H. Lee

S. S. Kim

C. S. Rhee

Predictors of bronchial hyperresponsiveness in chronic rhinosinusitis with nasal polyp

慢性鼻窦炎伴鼻息肉患者气道高反应性的预测因素

Abstract The impact of human IgE glycosylation on structure, function and disease mechanisms is not fully elucidated, and heterogeneity in different studies renders drawing conclusions challenging. Previous reviews discussed IgE glycosylation focusing on specific topics such as health versus disease, FcεR binding or impact on function. We present the first systematic review of human IgE glycosylation conducted utilizing the PRISMA guidelines. We sought to define the current consensus concerning the roles of glycosylation on structure, biology and disease. Despite diverse analytical methodologies, source, expression systems and the sparsity of data on IgE antibodies from non‐allergic individuals, collectively evidence suggests differential glycosylation profiles, particularly in allergic diseases compared with healthy states, and indicates functional impact, and contributions to IgE‐mediated hypersensitivities and atopic diseases. Beyond allergic diseases, dysregulated terminal glycan structures, including sialic acid, may regulate IgE metabolism. Glycan sites such as N394 may contribute to stabilizing IgE structure, with alterations in these glycans likely influencing both structure and IgE‐FcεR interactions. This systematic review therefore highlights critical IgE glycosylation attributes in health and disease that may be exploitable for therapeutic intervention, and the need for novel analytics to explore pertinent research avenues.

Alexandra J. McCraw

Lais C. G. F. Palhares

Jenifer L. Hendel

Richard A. Gardner

Aida Santaolalla

Silvia Crescioli

James McDonnell

Mieke Van Hemelrijck

Alicia Chenoweth

Daniel I. R. Spencer

Gerd K. Wagner

Sophia N. Karagiannis

<scp>I</scp>g<scp>E</scp> glycosylation and impact on structure and function: A systematic review

IgE糖基化及其对结构和功能的影响：一项系统综述

ABSTRACT Background Birch pollen (BP) interacts with airway epithelial cells to cause allergic sensitization and allergy in predisposed individuals. However, the basic mechanisms underlying the clinical effects are poorly understood. Changes in gene expression and cytokine secretion in nasal mucosal cells upon BP exposure were determined in BP‐allergic and non‐allergic individuals. Methods BP‐allergic ( n = 11) and non‐allergic individuals ( n = 12) participated in nasal provocations with saline and aqueous BP solution. Nasal scrapings and secretions were obtained at baseline and after BP provocation. Bulk RNA sequencing of the nasal scrapings was performed, and cytokines in nasal secretions were quantified. Results After BP challenge, we identified 160 differentially expressed genes (DEGs) in the nasal scrapings of allergic individuals and 44 in non‐allergic individuals. DEGs encoding S100 proteins, keratins, small proline‐rich repeat proteins, and cytokines were predominantly identified, with proinflammatory cytokine transcripts being upregulated only in the allergic cohort. The top canonical pathways in allergic individuals included granulocyte and agranulocyte adhesion and diapedesis, wound healing, IL‐8 signaling, and IL‐17‐related pathways. Enriched pathways in allergic participants were associated with granulocyte chemotaxis, humoral cell responses, and IL‐10, IL‐4, and IL‐13 signaling and were absent in non‐allergic individuals. At baseline and after BP challenge, higher amounts of CCL17, CCL20, CCL26, IL‐7, IL‐16, and IL‐33 were detected in nasal secretions of allergic compared to non‐allergic individuals. Conclusion Our results highlight the activation of important cellular signaling pathways specific to BP‐allergic individuals after BP exposure offering new perspectives for studying key players in BP allergy.

Srinidhi Sudharson

Julia Eckl‐Dorna

Anastasia Meshcheryakova

José Basílio

Sophia Derdak

Tanja Kalic

Nina Lengger

Nina Schweitzer

Diana Mechtcheriakova

Heimo Breiteneder

Christine Hafner

Transcriptomic Profiles of the Nasal Mucosa Following Birch Pollen Provocation Differ Between Birch Pollen‐Allergic and Non‐Allergic Individuals

桦树花粉激发后鼻黏膜转录组谱在桦树花粉过敏与非过敏个体之间存在差异

Food allergy (FA) is a major public health concern, estimated to affect up to 10% of the global population [1]. Cow's milk allergy (CMA) is the most common FA in younger children, with around 50% outgrowing the condition by the age of 5 ("natural tolerance") [2]. However, those who develop persisting CMA often have multiple allergic comorbidities and present with a more severe phenotype. As a result, in some countries, cow's milk is now the most common cause of fatal anaphylaxis in children and young people [3]. In these patients, historical management has been the complete elimination of milk and milk-containing products from the diet. More recently, oral immunotherapy (OIT) has been used to induce desensitisation and remission to the sensitising allergen [4]. OIT involves a gradual introduction of small amounts of the allergenic food (i.e., milk, peanut and egg) into the affected person's diet over time, leading to a state of desensitisation, and ideally longer-term remission (previously named 'sustained unresponsiveness') allowing the patient to consume the food ad libitum. This ultimately results in improved dietary flexibility and health-related quality of life. However, OIT is associated with significant challenges, including high rates of treatment-related adverse events including anaphylaxis, adherence issues as well as psychological and logistical implications and burden from the treatment. OIT for CMA appears to be a particular issue in terms of safety [5]. In addition, outcomes from OIT vary considerably among individuals, with some achieving significant benefits whereas others showing limited or no improvement [6]. Understanding the key immunological factors driving the response to OIT and identifying biomarkers that identify responders and non-responders and the induction of remission remains a key unmet need. The recent article entitled "Allergen-specific B cell responses in oral immunotherapy-induced desensitisation, remission, and natural outgrowth in cow's milk allergy" by Satitsuksanoa et al. [7] interrogated the trajectory profile of allergen-specific B cells during OIT (those who go on to reach desensitised or remission state) uniquely comparing these findings against the development of natural tolerance to the allergy. The study utilised time-course samples from children with CMA who received OIT, children who naturally outgrew CMA and healthy controls. In this seminal article, the authors revealed that albeit in small proportions, Bos 9-specific B cells are found in all patient groups investigated ruling out the common perception that allergen-specific cells are often confined to allergic individuals. Bos 9-specific B cells from healthy controls differ in that they are proficient in producing sIgG1 and sIgG4 but lack the ability to produce sIgE. Using a single cell transcriptomic approach to fully elucidate the molecular profile of Bos 9-specific B cells at these different stages of therapy, the authors demonstrated a clear difference in gene signatures between desensitised and remission groups, classifying them as distinct states post-OIT, with desensitisation being an earlier stage of remission. Specifically, the authors highlighted that IL10RA and TGFB3 were exclusively upregulated in desensitised OIT patients, whereas genes associated with B cell activation (i.e., RIF1, FOXP1, JAK3), BCR signalling (PIK3CA, PIK3CD, PRKCB) and B cell migration (CCR6) and differentiation (i.e., BCL11A, CARD11, DOCK11, MALT1) were downregulated in both desensitised and natural tolerance patient groups. Interestingly, the authors also highlighted TLR4, IGHG1, IGHA2 and IGHA2 as genes significantly upregulated in those who are in remission. Although OIT resulted in significant changes in gene signatures in those who reached remission state, the changes did not fully overlap with those seen in patients achieving natural tolerance. Finally, the authors employed proximity extension assay technology to reveal that allergen-specific B cells from those receiving OIT or those who developed natural tolerance had a higher capacity to produce IL-10 and TGF-b compared to healthy controls. Findings from this study offers new insight into the trajectory pathway of antigen-specific B cells over the course of OIT and the important role these cells play in those who develop a state of non-responsiveness. Furthermore, evidence from this study demonstrated that OIT is effective in modulating gene signatures beyond a desensitised state to somewhat mimic gene profiles seen in those who develop natural tolerance. As there is uncertainty as to the duration for which tolerance is maintained in remission post-OIT, this finding is of particular interest towards our understanding of natural tolerance and our ability to induce this ideal long-term state of tolerance that we all seek as a resolution for FA. These data support the assertion that the mechanisms of food allergen tolerance following OIT are similar—but not identical—to that resulting from natural tolerance. This leads to two important considerations: First, identifying genes that are in fact not rectified post-OIT compared to natural tolerance will ultimately provide us with a good grasp of how we could improve future therapies. Second, as clinicians, are we potentially interfering with natural tolerance and inducing a suboptimal state when we perform OIT in children who have a high probability of outgrowing their allergy naturally? For some foods, where dietary inclusion is very common (such as dairy), this may be less of a concern—in contrast to foods such as peanut where daily consumption is less common. Ultimately, this question can only be answered through further research to understand the mechanism of tolerance induction following OIT, and the validation of biomarkers more able to predict the likelihood of natural tolerance in food-allergic children. M.H.S. and J.A.L. drafted the initial manuscript. E.H.K., M.V.-O., and P.J.T. critically read and contributed to the writing of the manuscript. M.H.S. reports research grants from Immune Tolerance Network, Medical Research council, Allergy Therapeutics, LETI Laboratorios, Revolo Biotherapeutics, and lecture fees from Allergy Therapeutics and Leti Laboratorios. E.H.K. reports consulting fees from ALK-Abello, Allakos, Cellergy Pharma, DBV Technologies, Genentech, Hanimune Therapeutics, Novartis, Phylaxis BioScience, Revolo Biotherapeutics, and Ukko Inc., and research grants to his institution from NIH-NIAID and Food Allergy Research and Education (FARE). M.V.-O. receives research grants from Food Allergy Research and Education (FARE). P.J.T. declares grants from the UK Medical Research Council, the UK Food Standards Agency, The Jon Moulton Charity Trust, and the NIHR/Imperial Biomedical Research Centre, outside the submitted work, as well as personal fees from the UK Food Standards Agency, UpToDate, Elsevier, ALK, and Allergenis. J.A.L. reports grants from Biomedical Research Funding (Imperial College BRC). All declaration are outside the submitted work. The authors have nothing to report.

Mohamed H. Shamji

Edwin H. Kim

Marta Vazquez‐Ortiz

Paul J. Turner

Janice A. Layhadi

Allergen‐Specific B Cell Responses Following Desensitisation and Natural Tolerance to Cow's Milk Allergy

脱敏和自然耐受对牛奶过敏原特异性B细胞反应的影响

The airway epithelium serves as the first line of defense, protecting against airborne pathogens and pollutants while regulating immune responses. This layer comprises various cell types, including goblet cells, ciliated columnar cells, and basal cells. Airway basal stem cells have the ability to self-renew and differentiate into all pseudostratified epithelial cell types under both steady-state conditions and following acute injury [1-4]. Extensive and recurrent airway damage can induce fibrosis and stenosis, making normal function restoration challenging [5, 6]. Tissue engineering has shown promise in replacing irreversibly damaged airway epithelium, but no definitive methods have been established [7]. This study aimed to investigate the potential of a differentiated human airway epithelial layer graft to improve animal survival and reduce fibrosis in airway stenosis, offering a novel approach compared to conventional methods that focus on stem or mesenchymal stem cells. In our study, we investigated the efficacy of transplanting a fully differentiated human airway epithelial layer graft onto de-epithelialized trachea to enhance survival and maintain tracheal patency. First, we evaluated the protective effect of a fully differentiated human airway epithelial layer graft on de-epithelialized trachea (Figures S1 and S2). C57BL/6 mice were randomly divided into three groups: trachea with native intact epithelium (intact trachea group), de-epithelialized trachea (sham control group), or de-epithelialized trachea with transplanted human airway epithelial layer graft (graft group) (Figure 1A). The tracheal grafts were harvested from recipient mice on Day 14 post-transplantation for histological and immunohistochemical analyses. We observed the connection between the donor and host trachea under a microscope with hematoxylin–eosin (H&E) staining and found that they were anastomosed (Figure 1B, Figure S3). All animals in the intact trachea group survived, whereas four out of six mice died in the sham control group (Figure 1C). The tracheal lumen in the intact trachea group was not narrowed, and the mucosa of the trachea was similar to that of the host trachea. The lumen of the de-epithelialized trachea was narrowed, and granulation tissue proliferation was clearly observed (Figure 1D). The epithelial layer graft of fully differentiated human nasal cells to de-epithelialized trachea provided a better survival outcome, with only one animal out of six dying after surgery. An inflammatory response, characterized by an increased presence of neutrophils and macrophages, was observed in the de-epithelialized sham control trachea. In contrast, reduced inflammation and less fibrous proliferation was observed in the de-epithelialized trachea of the group that received an epithelial layer graft (Figure 1E,F). An epithelial surface was observed in all animals within the group that received an intact trachea (Figure 1B). STEM101-positive cells (a human nuclear marker) were found exclusively in the transplanted human airway epithelial layer graft (Figure 1G, Figure S3). Immunofluorescence staining demonstrated positive expression of ciliated (acetylated-tubulin positive) and basal (p63 positive) cells in both the intact trachea and graft groups (Figure 1H,I). This indicates that the transplanted human epithelial layer graft was successfully integrated into the de-epithelialized trachea. Next, we investigated any potential epithelial-derived cytokines that could suppress both inflammation and fibrosis. Recent studies have demonstrated that IL-37 plays a protective role against airway inflammation and fibrosis [8, 9]. IL-37 is a member of the IL-1 cytokine family that exhibits anti-inflammatory and immunosuppressive properties [10]. Treatment with recombinant IL-37 (50 ng/mL) inhibited the upregulated expression of α-smooth muscle actin (α-SMA) and collagen type I in NIH/3T3 cells induced by TGF-β1 (Figure S4). Furthermore, human airway epithelial cells co-cultured with NIH/3T3 cells suppressed TGF-β1-induced α-SMA and collagen type I expression. Notably, blocking IL-37 with a neutralizing antibody (20 μg/mL) restored α-SMA and collagen type I expression. These results demonstrate that IL-37 can inhibit fibroblast activation and reduce α-SMA and collagen type I production, in accordance with previous findings. To investigate the role of IL-37, we introduced lentiviral vectors into the airway epithelium (Figure S5). We initially assessed the transduction efficiency of small hairpin RNA targeting IL-37 in an ALI and discovered that fully differentiated airway epithelium transduced with lentiviral-mediated IL-37-specific small hairpin RNAs effectively inhibited IL-37 expression. To further confirm the function of epithelial-derived IL-37, C57BL/6 mice were subsequently randomly assigned to receive either de-epithelialized trachea or de-epithelialized trachea with a shControl or shIL37-treated epithelial layer graft (Figure 2A). Figure 2B,C display the results of in vivo experiments, revealing a significant impact of IL-37 knockdown on survival rates. Moreover, a noticeable increase in the number of neutrophils and macrophages was observed (Figure 2D,E). The human airway epithelial layer graft showed the presence of STEM101-positive cells in both the shControl and shIL-37-treated groups (Figure 2F). There was no significant difference in the number of ciliated cells between the two groups (Figure 2G). Immunofluorescence analysis revealed the presence of p63 with positive staining (Figure 2H). In the shCont-treated group, the human airway epithelial layer graft exhibited IL37-positive cells, while a decreased level of IL37-positive cells was seen in the shIL-37-treated group (Figure 2I and Figures S6 and S7). Epithelial cells play a crucial role in regeneration, primarily due to the differentiation potential of basal cells. Recent in vivo studies have specifically utilized epithelial basal cells, demonstrating their potential to seed artificial tracheas, leading to the formation of functional tracheal linings [11, 12]. These studies highlight the potential of epithelial cells in tissue engineering and regenerative medicine. Our study demonstrated that a fully differentiated human airway epithelial layer graft on a de-epithelialized trachea provides survival benefits and restores airway function in an animal model. In conclusion, a differentiated human airway epithelial layer graft has the potential to suppress fibrosis and improve animal survival in airway stenosis. Moreover, the beneficial effect of the epithelial layer graft is dependent on the expression of IL-37, suggesting that IL-37 could be a potential therapeutic target for airway stenosis. These findings suggest that this method could effectively treat airway diseases and injuries that result in tracheal epithelial damage. Conceptualization: H.-W. S. Methodology: R.K. Resources: D.W.K. Investigation: R.K. Animal experiments: R.K. and Y.S.K. Formal analysis and interpretation of data: R.K. and Y.S.K. Writing – original draft: R.K. Writing – review and editing: R.K. and H.-W.S. Supervision: H.-W.S. Funding acquisition: H.-W.S. This work was supported by a grant of the Korea Health Technology R&D Project through the Korea Health Industry Development Institute (KHIDI), funded by the Ministry of Health & Welfare, Republic of Korea (grant number: HI17C1669 and RS-2024-00439991) and a grant from the National Research Foundation of Korea (2022R1A4A3034038). R.K. and H.-W. S. have an intellectual property on the epithelial graft technique. Other author has declared that no conflicts of interest exist. The data that support the findings of this study are available from the corresponding author upon reasonable request. Figure S1. Figure S2. Figure S3. Figure S4. Figure S5. Figure S6. Figure S7. Data S1. Please note: The publisher is not responsible for the content or functionality of any supporting information supplied by the authors. Any queries (other than missing content) should be directed to the corresponding author for the article.

Roza Khalmuratova

Yi Sook Kim

Dae Woo Kim

Hyun‐Woo Shin

A Differentiated Epithelial Layer Graft Improves Fibrosis and Survival in Airway Stenosis via <scp>IL</scp>‐37

一种分化的上皮层移植物通过IL-37改善气道狭窄中的纤维化和生存率

The development of airway remodeling in asthma is believed to be a consequence of airway inflammation, including eosinophilia, a hallmark of asthma and asthma severity. We previously found that eosinophil products activate fibroblasts, with IL-1, oncostatin-M (OSM) and TNFSF12 as predicted eosinophilic factors responsible for fibroblast activation [1]. OSM, a member of the gp130 ligand family of cytokines, is produced by immune cells, but it is typically not recognized as an eosinophilic product. OSM has been associated with asthma severity and lower lung function [2], and it was reported that OSM upregulates gene expression levels that may promote airway granulocytic inflammation and mucus production [2]. In nasal polyps (NP) of patients with chronic rhinosinusitis (CRS), tissue OSM correlates with epithelial dysfunction and TSLP expression, but the main source in tissue appears to be the neutrophil [3, 4]. In our present study, we asked whether human blood eosinophils are a source of OSM and analyzed associations between OSM and airway eosinophilia, lung function, and other mediators in asthma. Blood eosinophils from nine allergic participants were cultured with IL-3 for 20 h. Then, eosinophils were seeded on heat-aggregated IgG for 6 h, which is a well-known model to induce robust degranulation and cytolysis of blood eosinophils [5]. Figure 1A (left panel) shows that in absence of IgG, eosinophils spontaneously released low but detectable amounts of OSM (median [interquartile range; IQR] of 9 pg/mL [4.0, 15.5]) while on IgG (IL3IgG), OSM secretion was 5-fold higher (median IQR of 47 pg/mL [39.5, 55]). Using 3′UTR RNA-seq, we analyzed OSM mRNA expression level in blood eosinophils activated in vitro with IL-3 or eotaxin-1 for 6 h. We found that IL-3 increased OSM expression level (3.5-fold versus no activation) (Figure 1A; right panel). Next, to establish a relationship between airway eosinophilia and OSM in vivo in a type-2 human model, we measured the amount of OSM protein in bronchoalveolar lavage (BAL) fluids (BALF) before and 48 h after a segmental bronchoprovocation with an allergen (SBP-Ag) in 18 subjects with mild asthma (previously described in [6]). OSM was detectable in most BALF before SBP-Ag (median IQR of 31 pg/mL [31,45]) and OSM amount increased after the challenge (median IQR of 78 pg/mL [35.5,186.5], p < 0.0001). The change in BALF OSM concentration after challenge was correlated with the change in concentration of BALF eosinophils (Figure 1B) and was inversely correlated with the change in lung function as determined using FEV1 (%P) (r = −0.676, p = 0.002; Table S1). Moreover, to analyze OSM protein in BALF vis-à-vis other well-known mediators of the immune response, 92 mediators were measured in BALF prepared before and after SBP-Ag using Olink Proteomics technology. Changes in BALF OSM strongly correlated with changes in TSLP, Lap-TGF-b1, chemokines, and proinflammatory cytokines (Figure 1C). Furthermore, changes in paired blood OSM amount correlated with changes in BALF OSM (Figure 1D), suggesting an inside-out mechanism with potential systemic impact following SBP-Ag. In Figure 2, we examined whether blood eosinophils displayed higher expression of OSM gene in severe asthma (n = 21) compared to healthy individuals (n = 19) and patients suffering from CRSwNP (n = 18) (Figure 2A). After adjustment for sex, expression level of OSM in isolated blood eosinophils was significantly elevated in severe asthma versus control and CRSwNP (Figure 2B), and OSM levels tended to correlate with two markers for loss of asthma control (ACQ and exacerbations) (Figure 2C). In conclusion, OSM is a product from activated eosinophils, and its expression is enhanced in eosinophils from patients with uncontrolled severe asthma. Airway OSM levels are associated with poorer lung function and multiple markers of inflammation and remodeling. This study should encourage further investigations on the role of OSM in asthma with the prospect that OSM, its inducer(s) or its downstream signaling becomes a drug target to treat eosinophilic asthma. All authors have made substantial contributions to conception and design, or acquisition of data, or analysis and interpretation of data; and have been involved in drafting the manuscript or revising it critically for important intellectual content; and have given final approval of the version to be published. Each author has participated sufficiently in the work to take public responsibility for appropriate portions of the content; and they agreed to be accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved. We thank the research participants from whom the data were acquired for their contributions to this work, the research nurse coordinators in the UW-Madison Clinical Core facility (P.I. Loren Denlinger) for subject recruitment and screening, and Paul Fichtinger for the preparation of blood eosinophils (P.I. Sameer Mathur). We thank Jean-Pascal Meneboo, Frédéric Leprêtre, and Martin Figeac (PLBS UAR 2014-US 41) for their implication in RNA-sequencing data processing. K. Bernau received funding from the Pulmonary Fibrosis Foundation, by an independent grant from Boehringer Ingelheim Pharmaceuticals Inc. who provided the financial support outside of the submitted work. W. W. Busse reports consulting fees/honoraria from GlaxoSmithKline, Regeneron, Sanofi, and Genentech, and royalties from Elsevier. N. N. Jarjour received research funding from AstraZeneca for extension of the National Institutes of Health–funded severe asthma research program; and received consulting fees over the past 3 years from GlaxoSmithKline, Chiese, and AstraZeneca related to asthma treatment. K. A. Dill-McFarland reports consulting fees from Seattle BioSoftware and EuropaDX related to computational tool development. F. Dezoteux was investigator for clinical trials sponsored by Abbvie, Almirall, Amgen, AstraZeneca, Eli Lilly, Galderma, Leo Pharma, Novartis, Pfizer, and Sanofi-Regeneron; received consulting fees by AbbVie, Almirall, Eli Lilly, Galderma, Leo Pharma, Novartis, Pfizer, Sanofi-Regeneron, and UCB. D. Staumont-Sallé received funding from AstraZeneca for a research study in DRESS syndrome; was investigator for clinical trials sponsored by Abbvie, Almirall, Amgen, AstraZeneca, Eli Lilly, Galderma, Leo Pharma, Novartis, Pfizer, and Sanofi-Regeneron; received consulting fees by AbbVie, Almirall, AstraZeneca, Eli Lilly, Galderma, GSK, Leo Pharma, Novartis, Pfizer, Sanofi-Regeneron, and UCB. C. Chenivesse declares research grants from AstraZeneca, GlaxoSmithKlein, Santelys, and Novartis, personal fees from ALK-Abello, AstraZeneca, Boehringer Ingelheim, Chiesi, Sanofi, and GlaxoSmithKlein and congress support from AstraZeneca, Boehringer Ingelheim, Chiesi, and Novartis. G. Lefèvre received consulting fees, personal fees for advisory boards or meetings, and research fundings from AstraZeneca and GSK. These relationships with pharmaceutical companies are not relevant to the current study. M. W. Johansson received funding from Hoffmann-La Roche, outside of the submitted work. The rest of the authors declare that they have no relevant conflicts of interest. All the data used in this manuscript are available to the public. Data S1. Please note: The publisher is not responsible for the content or functionality of any supporting information supplied by the authors. Any queries (other than missing content) should be directed to the corresponding author for the article.

Stephane Esnault

Ksenija Bernau

Heather L. Floerke

Arnaud Dendooven

Emeline Delaunay

Kimberly A. Dill‐McFarland

Matthew C. Altman

William W. Busse

Melissa A. Rosenkranz

Matthew C. Tattersall

Mats W. Johansson

Julien Labreuche

Delphine Beury

Shéhérazade Sebda

Frédéric Dezoteux

Baptiste Segard

Geoffrey Mortuaire

Delphine Staumont‐Sallé

Thomas Stoup

Cécile Chenivesse

Nathan Sandbo

Nizar N. Jarjour

Guillaume Lefèvre

Oncostatin‐M Is Produced by Human Eosinophils and Expression Is Increased in Uncontrolled Severe Asthma

人嗜酸性粒细胞产生抑瘤素-M，且在未控制的严重哮喘中表达增加

Little is known about metabolomic imbalances in eosinophilic esophagitis (EoE)—an allergen-mediated immunoinflammatory condition of the esophagus [1]. To address this knowledge gap, we conducted global untargeted salivary metabolomics in children with EoE. We analyzed saliva as oral mucosa is the initial interface between the triggering allergens and the host mucosal immune system. Additionally, saliva is rich in metabolites and is uniquely suited for noninvasive sampling, especially in children [2]. In an institutional review board-approved study (#151341), unstimulated saliva samples were collected from 28 children (6–18 years) with known EoE and symptoms of esophageal dysfunction immediately before their esophagogastroduodenoscopy (EGD). Participants were nil per os for > 6 h prior to their EGD. Demographic, clinical, endoscopic, and histologic features were also analyzed (Table 1). Per the current guidelines [3], 19 (68%) had EoE (active EoE [aEoE] = 9 [47%], and inactive EoE [iEoE] = 10 [53%]), and 9 (32%) were non-EoE controls (controls). Liquid chromatography-high-resolution mass spectrometry was used to analyze saliva samples. Downstream analyses of confidence levels 1, 2, and 3a identified compounds matching searched libraries or databases were performed (see Supporting Information for details) [4]. In all, an abundance of 434 compounds was significantly different ([p ≤ 0.05] with > 2-fold change [FC]) between EoE and controls, and PLS-DA identified well-defined clustering of salivary metabolites classifying the two groups. Ten compounds from endogenous origins belonging to nucleosides, nucleotides, organic acid derivatives, and organoheterocyclic compounds robustly differentiated EoE from controls. Specifically, 4-(Methylnitrosamino)-1-(3-pyridyl)-1-butanol (FC = 6.85; p = 0.003), and N-Heptanoylyglycine (FC = 3.62, p = 0.02), were significantly increased in EoE compared to controls. While deoxyadenosine (FC = −4.0, p = 0.01), deoxycytidine (FC = −3.42, p = 0.01), and adenosine (FC = −3.55, p = 0.02) were significantly lower in EoE than controls (Figure 1). Adenosine is known to have anti-inflammatory effects and is actively converted to inosine due to its long-term instability [5]. We hypothesize that a decrease in adenosine and a corresponding increase in inosine (inosine-41N5) in EoE (compared to control; FC = 1.24; p = 0.02) could be related to the underlying allergic inflammation. Next, 57 compounds differed between aEoE and iEoE. Of these, urea was significantly high (p = 0.03), and serylarginine was significantly low (p = 0.007) in aEoE compared to iEoE, suggesting that EoE activity can impact salivary metabolites (Figure 2b). Finally, we found 102 compounds with negative FC and 207 with positive FC differentiated aEoE from controls. Of these, eight molecules had a maximum fold-change of ≥ 3. All nucleotide molecules (including deoxyadenosine, deoxycytidine, adenosine, deoxyguanosine, and guanosine) showed significant negative FCs. In contrast, the organic acids and derivatives (such as urea, N-Heptanolyglycine, and L-Arginine) were significantly increased in aEoE compared to controls (Figure 2a). Arginine has an essential role in the inflammatory response, and esophageal microbiota of aEoE patients have a higher abundance of arginine, which treatment can disrupted [6]. A concurrent increase in salivary urea and arginine needs to be further investigated. The adenosine (p-value = 0.019, FC = 3.82) and pentadecanoylcarnitine (p-value = 0.031, FC = 3.38) were decreased in iEoE compared to controls. Pentadecanoylcarnitine is a fatty acid that plays a role in cellular metabolism, but its role in esophageal dysfunction remains to be understood. This is the first study to conduct global untargeted salivary metabolomics in children with EoE. We identified eight salivary metabolites of significant fold change altered in children with EoE compared to controls and two metabolites altered between aEoE and iEoE, irrespective of age and medication exposure. Studies with large sample sizes involving all ages and longitudinal follow-up are warranted to validate our findings and test their clinical utility. G.H. is a consultant to Bristol Myers Squibb, Regeneron, and Sanofi. The authors declare no conflicts of interest. The data that support the findings of this study are available from the corresponding author upon reasonable request. Data S1. Please note: The publisher is not responsible for the content or functionality of any supporting information supplied by the authors. Any queries (other than missing content) should be directed to the corresponding author for the article.

Abbreviation
Journal Impact	12.53
Quartiles(Global)	IMMUNOLOGY(Q1)

ISSN	0105-4538, 1398-9995
h-index	201
Top Journals	Yes

Publication Information	Publisher: Wiley-Blackwell Publishing Ltd，Publishing cycle: Monthly，Journal Type: journal，Open Access Journals: No
Basic data	Year of publication: 1948，Proportion of original research papers: 80.11%，Self Citation Rate:10.30%， Gold OA Rate: 49.51%
Average review cycle	网友分享经验：平均2月
Average recruitment ratio	网友分享经验：约50%

Allergy: European Journal of Allergy and Clinical Immunology

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