Journal of Allergy and Clinical Immunology最新文献

{"title":"Air pollution is associated with persistent peanut allergy in the first 10 years.","authors":"Diego J Lopez, Caroline J Lodge, Dinh S Bui, Nilakshi T Waidyatillake, John C Su, Luke D Knibbs, Rushani Wijesuriya, Kirsten P Perrett, Jennifer J Koplin, Victoria X Soriano, Kate Lycett, Yichao Wang, Katie Allen, Suzanne Mavoa, Shyamali C Dharmage, Adrian J Lowe, Rachel L Peters","doi":"10.1016/j.jaci.2024.08.018","DOIUrl":"10.1016/j.jaci.2024.08.018","url":null,"abstract":"<p><strong>Background: </strong>The role of air pollution in eczema and food allergy development remains understudied.</p><p><strong>Objective: </strong>We aimed to assess whether exposure to air pollution is associated with eczema and food allergies in the first 10 years of life.</p><p><strong>Methods: </strong>HealthNuts recruited a population-based sample of 1-year-old infants who were followed up at ages 4, 6, and 10 years. Annual average fine particulate matter (particulate matter with diameter of 2.5 μm or less, or PM_2.5) and nitrogen dioxide (NO₂) exposures were assigned to geocoded residential addresses. Eczema was defined by parent report. Oral food challenges to peanut, egg, and sesame were used to measure food allergy. Multilevel logistic regression models were fitted, and estimates were reported as adjusted odds ratios.</p><p><strong>Results: </strong>Those exposed to high concentration of NO₂ (<10 ppb) at age 1 year had higher peanut allergy prevalence at ages 1 (adjusted odds ratio [95% confidence interval], 2.21 [1.40-3.48]) and 4 (2.29 [1.28-4.11]) years. High exposure to NO₂ at 6 years old were associated with higher peanut allergy prevalence at age 6 (1.34 [1.00-1.82] per 2.7 ppb NO₂ increase) years. Similarly, increased PM_2.5 at age 1 year was associated with peanut allergy at ages 4, 6, and 10 years (respectively, 1.27 [1.01-1.60], 1.27 [1.01-1.56], and 1.46 [1.05-2.04] per 1.2 μg/m PM_2.5 increase) years. We found that increased concentrations of NO₂ or PM_2.5 at age 1 year were associated with persistent peanut allergy at later ages. Little evidence of associations was observed with eczema or with egg allergy.</p><p><strong>Conclusions: </strong>Early-life exposure to PM_2.5 and NO₂ was associated with peanut allergy prevalence and persistence. Policies aiming at reducing air pollution could potentially reduce presence and persistence of peanut allergy.</p>","PeriodicalId":14936,"journal":{"name":"Journal of Allergy and Clinical Immunology","volume":" ","pages":"1489-1499.e9"},"PeriodicalIF":11.4,"publicationDate":"2024-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142500841","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Metabolic dysfunction mediated by HIF-1α contributes to epithelial differentiation defects in eosinophilic esophagitis.","authors":"Sinéad Ryan, Louise Crowe, Sofía N Almeida Cruz, Matthew D Galbraith, Carol O'Brien, Juliet A Hammer, Ronan Bergin, Shauna K Kellett, Gary E Markey, Taylor M Benson, Olga Fagan, Joaquin M Espinosa, Niall Conlon, Claire L Donohoe, Susan McKiernan, Andrew E Hogan, Eóin N McNamee, Glenn T Furuta, Calies Menard-Katcher, Joanne C Masterson","doi":"10.1016/j.jaci.2024.07.030","DOIUrl":"10.1016/j.jaci.2024.07.030","url":null,"abstract":"<p><strong>Background: </strong>Investigating the contributory role that epithelial cell metabolism plays in allergic inflammation is a key factor to understanding what influences dysfunction and the pathogenesis of the allergic disease eosinophilic esophagitis (EoE). We previously highlighted that the absence of hypoxia signaling through hypoxia-inducible factor (HIF)-1α in EoE contributes to esophageal epithelial dysfunction. However, metabolic regulation by HIF-1α has not been explored in esophageal allergy.</p><p><strong>Objectives: </strong>We sought to define the role of HIF-1α-mediated metabolic dysfunction in esophageal epithelial differentiation processes and barrier function in EoE.</p><p><strong>Methods: </strong>In RNA sequencing of EoE patient biopsy samples, we observed the expression pattern of key genes involved in mitochondrial metabolism/oxidative phosphorylation (OXPHOS) and glycolysis. Seahorse bioenergetics analysis was performed on EPC2-hTERT cells to decipher the metabolic processes involved in epithelial differentiation processes. In addition, air-liquid interface cultures were used to delineate metabolic dependency mechanisms required for epithelial differentiation.</p><p><strong>Results: </strong>Transcriptomic analysis identified an increase in genes associated with OXPHOS in patients with EoE. Epithelial origin of this signature was confirmed by complex V immunofluorescence of patient biopsy samples. Bioenergetic analysis in vitro revealed that differentiated epithelium was less reliant on OXPHOS compared with undifferentiated epithelium. Increased OXPHOS potential and reduced glycolytic capacity was mirrored in HIF1A-knockdown EPC2-hTERT cells that exhibited a significant absence of terminal markers of epithelial differentiation, including involucrin. Pharmacologic glucose transport inhibition phenocopied this, while rescue of the HIF-1α-deficient phenotype using the pan-prolyl hydroxylase inhibitor dimethyloxalylglycine resulted in restored expression of epithelial differentiation markers.</p><p><strong>Conclusions: </strong>An OXPHOS-dominated metabolic pattern in EoE patients, brought about largely by the absence of HIF-1α-mediated glycolysis, is linked with the deficit in esophageal epithelial differentiation.</p>","PeriodicalId":14936,"journal":{"name":"Journal of Allergy and Clinical Immunology","volume":" ","pages":"1472-1488"},"PeriodicalIF":11.4,"publicationDate":"2024-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142107710","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"IL-4 acts on skin-derived dendritic cells to promote the T_H2 response to cutaneous sensitization and the development of allergic skin inflammation.","authors":"Juan Manuel Leyva-Castillo, Mrinmoy Das, Maria Strakosha, Alex McGurk, Emilie Artru, Christy Kam, Mohammed Alasharee, Duane R Wesemann, Michio Tomura, Hajime Karasuyama, Frank Brombacher, Raif S Geha","doi":"10.1016/j.jaci.2024.06.021","DOIUrl":"10.1016/j.jaci.2024.06.021","url":null,"abstract":"<p><strong>Background: </strong>Atopic dermatitis is characterized by scratching and a T_H2-dominated local and systemic response to cutaneously encountered antigens. Dendritic cells (DCs) capture antigens in the skin and rapidly migrate to draining lymph nodes (dLNs) where they drive the differentiation of antigen-specific naive T cells.</p><p><strong>Objective: </strong>We sought to determine whether non-T-cell-derived IL-4 acts on skin-derived DCs to promote the T_H2 response to cutaneously encountered antigen and allergic skin inflammation.</p><p><strong>Methods: </strong>DCs from dLNs of ovalbumin (OVA)-exposed skin were analyzed by flow cytometry and for their ability to polarize OVA-specific naive CD4⁺ T cells. Skin inflammation following epicutaneous sensitization of tape-stripped skin was assessed by flow cytometry of skin cells and real-time quantitative PCR of cytokines. Cytokine secretion and antibody levels were evaluated by ELISA.</p><p><strong>Results: </strong>Scratching upregulated IL4 expression in human skin. Similarly, tape stripping caused rapid basophil-dependent upregulation of cutaneous Il4 expression in mouse skin. In vitro treatment of DCs from skin dLNs with IL-4 promoted their capacity to drive T_H2 differentiation. DCs from dLNs of OVA-sensitized skin of Il4^-/- mice and CD11c-CreIl4r^flox/- mice, which lack IL-4Rα expression in DCs (DC^Δ/Δll4ra mice), were impaired in their capacity to drive T_H2 polarization compared with DCs from controls. Importantly, OVA-sensitized DC^Δ/Δll4ra mice demonstrated impaired allergic skin inflammation and OVA-specific systemic T_H2 response evidenced by reduced T_H2 cytokine secretion by OVA-stimulated splenocytes and lower levels of OVA-specific IgE and IgG1 antibodies, compared with controls.</p><p><strong>Conclusions: </strong>Mechanical skin injury causes basophil-dependent upregulation of cutaneous IL-4. IL-4 acts on skin DCs that capture antigen and migrate to dLNs to promote their capacity for T_H2 polarization and drive allergic skin inflammation.</p>","PeriodicalId":14936,"journal":{"name":"Journal of Allergy and Clinical Immunology","volume":" ","pages":"1462-1471.e3"},"PeriodicalIF":11.4,"publicationDate":"2024-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11625010/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141599884","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"IL-4 and dendritic cells in atopic dermatitis: Old dogs learn new tricks.","authors":"Donata Vercelli","doi":"10.1016/j.jaci.2024.10.001","DOIUrl":"10.1016/j.jaci.2024.10.001","url":null,"abstract":"","PeriodicalId":14936,"journal":{"name":"Journal of Allergy and Clinical Immunology","volume":" ","pages":"1419-1421"},"PeriodicalIF":11.4,"publicationDate":"2024-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142400313","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Indoor allergen exposure and its association to upper respiratory infections and pulmonary outcomes among children with asthma.","authors":"Darlene Bhavnani, Travis Lilley, Paul J Rathouz, Sylvie Beaudenon-Huibregtse, Meghan F Davis, Meredith C McCormack, Corinne A Keet, Susan Balcer-Whaley, Michelle Newman, Elizabeth C Matsui","doi":"10.1016/j.jaci.2024.08.006","DOIUrl":"10.1016/j.jaci.2024.08.006","url":null,"abstract":"<p><strong>Background: </strong>Certain environmental allergen exposures are more common in disadvantaged communities and may contribute to differences in susceptibility to upper respiratory infections (URIs).</p><p><strong>Objectives: </strong>We examined associations between indoor allergens and: (1) URI; (2) URI + cold symptoms; (3) URI + cold symptoms + pulmonary eosinophilic inflammation (fraction of exhaled nitric oxide ≥20 ppb); and (4) URI + cold symptoms + reduced lung function (percent predicted forced expiratory volume in 1 second of <80%).</p><p><strong>Methods: </strong>We used data from the Environmental Control as Add-on Therapy for Childhood Asthma (ECATCh) study. Allergen concentrations were measured in air (mouse) and settled dust (mouse, cockroach, dog, and cat). URI was determined by testing nasal mucus for upper respiratory viruses. We evaluated associations between allergen concentrations and URI-associated outcomes accounting for age, sex, study month, season, health insurance, and household size.</p><p><strong>Results: </strong>Ninety participants (92% Black, 92% public insurance) with 192 observations were included; 52 (27%) of observations were positive for URI. A doubling in cockroach allergen concentration increased the odds of a URI with cold symptoms by 18% (odds ratio [OR] = 1.18, 95% confidence interval [CI], 0.99-1.40), the odds of a URI + cold symptoms + pulmonary eosinophilic inflammation by 31% (OR = 1.31, 95% CI, 1.10-1.57), and the odds of a URI + cold symptoms + reduced lung function by 45% (OR = 1.45, 95% CI, 1.13-1.85). Mouse allergen concentrations were positively associated with all outcomes. Associations were suggestively stronger among children sensitized to pest allergens.</p><p><strong>Conclusions: </strong>Cockroach and mouse, but not dog or cat, allergen exposure may predispose children with asthma to URIs with colds and lower respiratory outcomes.</p>","PeriodicalId":14936,"journal":{"name":"Journal of Allergy and Clinical Immunology","volume":" ","pages":"1434-1441"},"PeriodicalIF":11.4,"publicationDate":"2024-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142017602","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"The Editors' Choice.","authors":"","doi":"10.1016/j.jaci.2024.10.014","DOIUrl":"https://doi.org/10.1016/j.jaci.2024.10.014","url":null,"abstract":"","PeriodicalId":14936,"journal":{"name":"Journal of Allergy and Clinical Immunology","volume":"154 6","pages":"1409-1413"},"PeriodicalIF":11.4,"publicationDate":"2024-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142791384","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Consensus of the Italian Primary Immunodeficiency Network on the use and interpretation of genetic testing for the diagnosis of inborn errors of immunity (IEI).","authors":"Giuliana Giardino, Gigliola Di Matteo, Silvia Giliani, Simona Ferrari, Vassilios Lougaris, Raffaele Badolato, Francesca Conti, Roberta Romano, Maria Pia Cicalese, Silvia Ricci, Federica Barzaghi, Antonio Marzollo, Cristina Cifaldi, Davide Montin, Lorenzo Lodi, Emilia Cirillo, Baldassarre Martire, Antonio Trizzino, Mayla Sgrulletti, Viviana Moschese, Marika Comegna, Giuseppe Castaldo, Alberto Tommasini, Chiara Azzari, Caterina Cancrini, Alessandro Aiuti, Claudio Pignata","doi":"10.1016/j.jaci.2024.11.030","DOIUrl":"https://doi.org/10.1016/j.jaci.2024.11.030","url":null,"abstract":"<p><strong>Background: </strong>Inborn errors of immunity (IEIs) are more than 500 different rare congenital disorders of the immune system characterized by susceptibility to infections and immune dysregulation. The significant overlap of the clinical features among the different forms may lead to diagnostic delay. High throughput sequencing techniques may allow a timely genetic definition. Guidelines for the use and the interpretation of genetic testing produced by the American College of Medical Genetics and Genomics (ACMG) and the European Society of Human Genetics (ESHG) do not cover specificities for the application to IEIs.</p><p><strong>Objective: </strong>The aim of this consensus study is to define the best approach to genetic testing for IEIs.</p><p><strong>Methods: </strong>A panel of experts in the context of the Italian Primary Immunodeficiency Network (IPINet) composed a list of statements that were evaluated using Delphi method.</p><p><strong>Results: </strong>The experts recommend that genetic testing for IEIs should be offered to selected patients with warning signs for IEIs and highlight the crucial role of thorough phenotyping and functional tests for the conclusive diagnosis of IEI. Comprehensive educational programs targeted to health care professionals and the public should be developed to increase IEIs awareness and reduce the diagnostic delay. Ethical issues should be pondered over the diagnostic advantages of genetic tests requested for diagnostic purposes.</p><p><strong>Conclusion: </strong>Adherence to the guidelines on the use and interpretation of genetic testing for the diagnosis of IEIs should help limiting the inappropriate use of these techniques and reduce the risk of misdiagnosis and apprehension for inconclusive genetic results.</p>","PeriodicalId":14936,"journal":{"name":"Journal of Allergy and Clinical Immunology","volume":" ","pages":""},"PeriodicalIF":11.4,"publicationDate":"2024-11-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142769157","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Features of hyperinflammation link the biology of EBV infection and cytokine storm syndromes.","authors":"Meng Liu, Kailey E Brodeur, Jacob R Bledsoe, Claudia N Harris, Jill Joerger, Rachel Weng, Evan E Hsu, Michael T Lam, Casey A Rimland, Courtney E LeSon, Jian Yue, Lauren A Henderson, Fatma Dedeoglu, Jane W Newburger, Peter A Nigrovic, Mary Beth F Son, Pui Y Lee","doi":"10.1016/j.jaci.2024.11.029","DOIUrl":"https://doi.org/10.1016/j.jaci.2024.11.029","url":null,"abstract":"<p><strong>Background: </strong>Overt immune activation by viral infections can lead to cytokine storm syndromes, such as hemophagocytic lymphohistiocytosis (HLH) and macrophage activation syndrome (MAS).</p><p><strong>Objective: </strong>We aim to compare the immune response to different viral pathogens to understand the connection between infections and cytokine storm syndromes.</p><p><strong>Methods: </strong>We recruited children who presented to the emergency room with fever for ≥ 3 days. We performed immune profiling using Olink proximity extension assay and flow cytometry. We compared the findings with cases of HLH, MAS, Kawasaki disease (KD), and multisystem inflammatory syndrome in children (MIS-C).</p><p><strong>Results: </strong>We enrolled 352 febrile patients and studied 110 cases with confirmed common viral infections. We found that Epstein-Barr virus (EBV) uniquely triggered high levels of multiple cytokines (IL-18, IL-27, tumor necrosis factor, FLT3 ligand, and lymphotoxin alpha) and IFN-γ-induced chemokines (CXCL9/10/11 and CCL19). These patterns are similar to the hyperinflammatory response associated with HLH / MAS, but less consistent with the findings in KD and MIS-C. Flow cytometry analysis revealed that CD38⁺HLA-DR⁺ T lymphocytes, which are pathogenic cells responsible for IFN-γ production in HLH / MAS, are vastly expanded in patients with acute EBV infection. Cell sorting identified CD38⁺HLA-DR⁺ T cells as atypical lymphocytes that are classically associated with acute EBV infection.</p><p><strong>Conclusion: </strong>This work broadens our understanding of common viral infections in children and provides an immunologic basis for the link between EBV infection and HLH / MAS.</p>","PeriodicalId":14936,"journal":{"name":"Journal of Allergy and Clinical Immunology","volume":" ","pages":""},"PeriodicalIF":11.4,"publicationDate":"2024-11-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142769122","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Inborn errors of immunity reveal molecular requirements for generation and maintenance of human CD4⁺ IL-9-expressing cells.","authors":"Geetha Rao, Corinne D Mack, Tina Nguyen, Natalie Wong, Kathryn Payne, Lisa Worley, Paul E Gray, Melanie Wong, Peter Hsu, Michael O Stormon, Kahn Preece, Daniel Suan, Michael O'Sullivan, Annaliesse K Blincoe, Jan Sinclair, Satoshi Okada, Sophie Hambleton, Peter D Arkwright, Kaan Boztug, Polina Stepensky, Megan A Cooper, Liliana Bezrodnik, Kari C Nadeau, Hassan Abolhassani, Roshini S Abraham, Mikko R J Seppänen, Vivien Béziat, Jacinta Bustamante, Lisa R Forbes Satter, Jennifer W Leiding, Isabelle Meyts, Emmanuelle Jouanguy, Stéphanie Boisson-Dupuis, Gulbu Uzel, Anne Puel, Jean-Laurent Casanova, Stuart G Tangye, Cindy S Ma","doi":"10.1016/j.jaci.2024.11.031","DOIUrl":"10.1016/j.jaci.2024.11.031","url":null,"abstract":"<p><strong>Background: </strong>CD4⁺ T cells play essential roles in adaptive immunity. Distinct CD4⁺ T-cell subsets-T_H1, T_H2, T_H17, T_H22, T follicular helper, and regulatory T cells-have been identified, and their contributions to host defense and immune regulation are increasingly well defined. IL-9-producing T_H9 cells were first described in 2008 and appear to play both protective and pathogenic roles in human immunity. However, key requirements for generating human T_H9 cells remain incompletely defined.</p><p><strong>Objective: </strong>We sought to define signaling pathways that regulate IL-9 production by human CD4⁺ T cells.</p><p><strong>Methods: </strong>Human naive and memory CD4⁺ T cells were cultured under different conditions, and the molecular mechanisms regulating IL-9 induction were determined by assessing the ability of CD4⁺ T cells from a broad range of patients (n = 92) with pathogenic variants in key immune genes (n = 21) to differentiate into IL-9⁺ cells.</p><p><strong>Results: </strong>We identified 2 culture conditions that yielded IL-9-expressing cells from naive CD4⁺ T cells and amplified IL-9 production by in vivo-generated memory CD4⁺ T cells: TGF-β plus IL-4 (ie, T_H9 polarizing condition), and the combination of IL-21, IL-23, IL-6, IL-1β, and TGF-β (ie, T_H17 polarizing condition). Combining these conditions had a synergistic effect in generating IL-9⁺CD4⁺ T cells. IL-9 induction required STAT3-activating cytokines as well as intact signaling via the T-cell receptor and STAT5. Importantly, IL-9 induction was restrained by IFN-γ/STAT1 and IL-10.</p><p><strong>Conclusions: </strong>Our findings revealed critical molecules involved in inducing/restraining IL-9 production by human CD4⁺ T cells, thereby identifying pathways that could be targeted to modulate IL-9 in health and disease.</p>","PeriodicalId":14936,"journal":{"name":"Journal of Allergy and Clinical Immunology","volume":" ","pages":""},"PeriodicalIF":11.4,"publicationDate":"2024-11-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142769124","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Eosinophilic Esophagitis Drives Tissue Fibroblast Regenerative Programs Towards Pathologic Dysfunction.","authors":"Medet Jumabay, Edsel M Abud, Kevin Okamoto, Paramita Dutta, Austin W T Chiang, Haining Li, Mario Manresa, Yanfang P Zhu, Dana Frederick, Richard Kurten, Ben Croker, Nathan E Lewis, Joshua L Kennedy, Ranjan Dohil, Michael Croft, Ferhat Ay, Joshua B Wechsler, Seema S Aceves","doi":"10.1016/j.jaci.2024.11.028","DOIUrl":"https://doi.org/10.1016/j.jaci.2024.11.028","url":null,"abstract":"<p><strong>Background: </strong>Pathologic tissue remodeling with scarring and tissue rigidity has been demonstrated in inflammatory, autoimmune, and allergic diseases. Eosinophilic esophagitis (EoE) is an allergic disease that is diagnosed and managed by repeated biopsy procurement, allowing an understanding of tissue fibroblast dysfunction. While EoE associated tissue remodeling causes clinical dysphagia, food impactions and esophageal rigidity and strictures, molecular mechanisms driving these complications remain under investigation.</p><p><strong>Objective: </strong>We hypothesized that chronic EoE inflammation induces pathogenic fibroblasts with dysfunctional tissue regeneration and motility.</p><p><strong>Methods: </strong>We used single cell RNA sequence (scRNA-Seq), fluorescence activated cell sorting analysis, and fibroblast differentiation and migration assays to decipher the induced and retained pathogenic dysfunctions in EoE versus healthy esophageal fibroblasts.</p><p><strong>Results: </strong>Differentiation assays demonstrated that active EoE fibroblasts retain regenerative programs for rigid cells such as chondrocytes (p<0.05) but lose healthy fibroblast capacity for soft cells such as adipocytes (p<0.01) which was reflected in biopsy immunostaining (p<0.01). EoE, but not healthy, fibroblasts have pro-inflammatory and pro-rigidity transcriptional programs on scRNA-Seq. In vivo, regenerative fibroblasts reside in perivascular regions and near the epithelial junction and, during EoE, have significantly increased migration (p<0.01). Flow analysis and functional assays demonstrated that regenerative EoE fibroblasts have decreased surface CD73 expression and activity (both p<0.05) compared to healthy, indicating aberrant ATP handling. EoE fibroblast dysfunctions were induced in healthy fibroblasts by reducing CD73 activity and rescued in EoE using adenosine repletion.</p><p><strong>Conclusion: </strong>A normalization of perturbed extracellular ATP handling and CD73 could improve pathogenic fibroblast dysfunction and tissue regeneration in type 2 inflammatory diseases.</p>","PeriodicalId":14936,"journal":{"name":"Journal of Allergy and Clinical Immunology","volume":" ","pages":""},"PeriodicalIF":11.4,"publicationDate":"2024-11-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142769159","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}