Journal of Allergy and Clinical Immunology最新文献

{"title":"Analysis of human neutrophils from nasal polyps by single-cell RNA sequencing reveals roles of neutrophils in chronic rhinosinusitis","authors":"Naruhito Iwasaki MD, PhD ,&nbsp;Julie A. Poposki MS ,&nbsp;Masanori Kidoguchi MD, PhD ,&nbsp;Aiko Oka MD, PhD ,&nbsp;Aiko I. Klingler PhD ,&nbsp;Whitney W. Stevens MD, PhD ,&nbsp;Lydia A. Suh MS ,&nbsp;Junqin Bai PhD ,&nbsp;Anju T. Peters MD ,&nbsp;Leslie C. Grammer MD ,&nbsp;Kevin C. Welch MD ,&nbsp;Stephanie S. Smith MD ,&nbsp;David B. Conley MD ,&nbsp;Bruce S. Bochner MD ,&nbsp;Robert P. Schleimer PhD ,&nbsp;Robert C. Kern MD ,&nbsp;Bruce K. Tan MD, MS ,&nbsp;Atsushi Kato PhD","doi":"10.1016/j.jaci.2024.10.032","DOIUrl":"10.1016/j.jaci.2024.10.032","url":null,"abstract":"<div><h3>Background</h3><div>Chronic rhinosinusitis with nasal polyps (CRSwNP) is characterized by type 2 (T2) inflammation. Recent studies, including our own, suggest that neutrophils are also elevated in T2 nasal polyps (NP) and that elevated neutrophils display an activated phenotype. However, the actual roles of neutrophils in NP pathogenesis in T2 CRSwNP are still largely unclear.</div></div><div><h3>Objective</h3><div>To reveal the roles and heterogeneity of neutrophils in NP tissue by single-cell RNA sequencing analysis.</div></div><div><h3>Methods</h3><div>We developed a novel microwell-based single-cell RNA sequencing assay using granulocyte-enriched samples from 5 control sinus tissues, 5 NP tissues and patient-matched peripheral blood (PB) samples. This approach allowed for examination of differential expression of genes in NP neutrophils by the Benjamini-Hochberg algorithm and predicted the overall function of NP neutrophils by pathway and Gene Ontology enrichment analyses.</div></div><div><h3>Results</h3><div>After performing all quality control steps, we successfully detected neutrophils. We identified 333 downregulated and 128 upregulated genes in NP neutrophils (1,151 cells) compared with all PB neutrophils (13,591 cells) (&gt;1.5-fold, <em>q</em> &lt; 0.05) and found commonly dysregulated genes in NP neutrophils compared with both all PB and control sinus tissue neutrophils (3,136 cells). Commonly downregulated genes in NP neutrophils were associated with the innate immune system, and upregulated genes were associated with nuclear factor-κB signaling, cytokine activity, and cellular response to oxygen-containing compounds. NP neutrophils displayed 4 clusters revealing potential heterogeneity of neutrophils in NP tissue.</div></div><div><h3>Conclusions</h3><div>Elevated neutrophils in NP tissue appear to exist in several subphenotypes that may play important pathogenic roles in CRSwNP.</div></div>","PeriodicalId":14936,"journal":{"name":"Journal of Allergy and Clinical Immunology","volume":"155 3","pages":"Pages 843-855"},"PeriodicalIF":11.4,"publicationDate":"2025-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142620952","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":"Baseline epitope-specific IgE profiles are predictive of sustained unresponsiveness or high threshold 1-year post oral immunotherapy in the POISED trial","authors":"Maria Suprun PhD ,&nbsp;Ashley Sang Eun Lee MD ,&nbsp;Robert Getts PhD ,&nbsp;Simon Peck BS ,&nbsp;Sayantani B. Sindher MD ,&nbsp;Kari C. Nadeau MD, PhD ,&nbsp;R. Sharon Chinthrajah MD ,&nbsp;Stephen J. Galli MD ,&nbsp;Hugh A. Sampson MD","doi":"10.1016/j.jaci.2024.10.017","DOIUrl":"10.1016/j.jaci.2024.10.017","url":null,"abstract":"<div><h3>Background</h3><div>Results from the POISED trial suggest that discontinuation of peanut oral immunotherapy can increase the risk of regaining clinical reactivity to peanut.</div></div><div><h3>Objective</h3><div>We sought to determine whether patients who achieved sustained unresponsiveness (SU) or sustained high threshold (SHT) have different baseline sequential epitope-specific IgE profiles than patients who achieved transient desensitization.</div></div><div><h3>Methods</h3><div>Subjects in the POISED trial (NCT02103270) were randomized to peanut (n = 95) or placebo (n = 25) for 24 months. Oral immunotherapy–desensitized subjects were then assigned to no peanut (PN-0) (n = 51) or 300 mg peanut (PN-300) (n = 30) for 12 months. SU and SHT were determined by subjects in PN-0 and PN-300, respectively, passing 4000-mg peanut oral challenge. Specific IgE and IgG₄ levels to peanut; Ara h 1, Ara h 2, and Ara h 3 proteins; and 64 allergenic epitopes were measured. We developed machine learning models with bootstrap simulations using baseline data to predict SU/SHT.</div></div><div><h3>Results</h3><div>Of 80 (84%) subjects who were desensitized to peanut, 13% (n = 8) and 37% (n = 13) achieved SU/SHT in PN-0 and PN-300 groups. Decreases in epitope-and protein-specific IgE levels and increases in IgG₄ levels were observed during 2 years of oral immunotherapy. At baseline, patients with SU in PN-0, but not PN-300, group had lower epitope-specific IgE and protein-specific IgE levels compared with the transient desensitization group. A machine learning model with 12 baseline epitope-specific IgEs and age could predict SU/SHT with accuracy of 94%, area under the curve 0.97, sensitivity 1.00, and specificity 0.91.</div></div><div><h3>Conclusions</h3><div>Subjects who achieved SU/SHT had different baseline protein- and epitope-specific IgE profiles than subjects with transient desensitization. These profiles may help identify patients with an increased likelihood of achieving SU/SHT.</div></div>","PeriodicalId":14936,"journal":{"name":"Journal of Allergy and Clinical Immunology","volume":"155 3","pages":"Pages 923-931.e2"},"PeriodicalIF":11.4,"publicationDate":"2025-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142590625","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":"MRGPRX2 facilitates IgE-mediated systemic anaphylaxis in a newly established knock-in mouse model","authors":"Maram Bawazir BDS ,&nbsp;Sangita Sutradhar PhD ,&nbsp;Saptarshi Roy PhD ,&nbsp;Hydar Ali PhD","doi":"10.1016/j.jaci.2024.11.021","DOIUrl":"10.1016/j.jaci.2024.11.021","url":null,"abstract":"<div><h3>Background</h3><div>In addition to FcεRI, a subtype of human mast cells (MCs) expresses Mas-related G protein–coupled receptor X2 (MRGPRX2; mouse counterpart MrgprB2). Although MrgprB2 contributes to IgE-mediated passive systemic anaphylaxis (PSA) <em>in vivo</em>, an MRGPRX2 inhibitor, compound 9 (C9), does not block MrgprB2- or IgE-mediated MC degranulation <em>in vitro</em>.</div></div><div><h3>Objective</h3><div>Our aim was to generate mice expressing human MRGPRX2 to study receptor function <em>in vitro</em> and PSA <em>in vivo</em>.</div></div><div><h3>Methods</h3><div>The clustered regularly interspaced short palindromic repeats (CRISPR)/Cas9-mediated gene editing approach was utilized to replace endogenous MrgprB2 with human MRGPRX2 in mice (MRGPRX2-KI mice). MRGPRX2 expression in the skin, gingiva, trachea, and colon were evaluated by using an anti-human MRGPRX2 antibody. Peritoneal MCs (PMCs) cultured from wild-type, MRGPRX2-KI, and MrgprB2^−/− mice were used to study agonists-induced degranulation. The effects of selective MRGPRX2 inhibitors (C9 and compound 9-6 [C9-6]) on substance P– or IgE-mediated MC degranulation <em>in vitro</em> and IgE-mediated PSA <em>in vivo</em> were tested.</div></div><div><h3>Results</h3><div>MRGPRX2-expressing MCs were present in tissues of MRGPRX2-KI mice. Most of the agonists tested induced greater degranulation at lower concentrations in PMCs from MRGPRX2-KI mice than in cells from wild-type mice. Furthermore, C9 and C9-6 inhibited degranulation in MRGPRX2-KI PMCs in response to substance P. In contrast, they had no effect on IgE-mediated degranulation <em>in vitro</em> but did inhibit PSA in MRGPRX2-KI mice <em>in vivo</em>.</div></div><div><h3>Conclusions</h3><div>MRGPRX2-KI mice provide a readily available source of primary MCs for signaling studies. Furthermore, transactivation of MRGPRX2 contributes to IgE-mediated PSA, suggesting that MRGPRX2-KI mice could be utilized as a preclinical model for testing novel therapeutics targeting MRGPRX2 and its cross talk with FcεRI.</div></div>","PeriodicalId":14936,"journal":{"name":"Journal of Allergy and Clinical Immunology","volume":"155 3","pages":"Pages 974-987.e1"},"PeriodicalIF":11.4,"publicationDate":"2025-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142710270","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":"Leptin augments IL-13–induced airway eotaxins and submucosal eosinophilia in obesity-associated asthma","authors":"Jennifer L. Ingram PhD ,&nbsp;Victoria L. McQuade MRes ,&nbsp;Jasmine Weiss MD, MHS ,&nbsp;Jack T. Womble BS ,&nbsp;Mark D. Ihrie PhD ,&nbsp;Karen Zhao BS ,&nbsp;Dave Francisco BS ,&nbsp;Barbara Theriot MS ,&nbsp;Katelynn May BSN ,&nbsp;Haein Kim BS ,&nbsp;Matthew McCravy MD ,&nbsp;Maor Sauler MD ,&nbsp;Njira L. Lugogo MD ,&nbsp;Mary E. Sunday MD, PhD ,&nbsp;Jeffrey Everitt DVM ,&nbsp;Julia K.L. Walker PhD ,&nbsp;Robert M. Tighe MD ,&nbsp;Monica Kraft MD ,&nbsp;Loretta G. Que MD","doi":"10.1016/j.jaci.2024.10.039","DOIUrl":"10.1016/j.jaci.2024.10.039","url":null,"abstract":"<div><h3>Background</h3><div>Airway tissue eosinophilia can be an observed feature of obesity-associated type 2 (T2) asthma, but the processes mediating this inflammation are unknown.</div></div><div><h3>Objective</h3><div>To investigate a process whereby leptin, an adipokine elevated in obesity, potentiates pulmonary eosinophilia and eotaxin production by airway fibroblasts in T2 asthma.</div></div><div><h3>Methods</h3><div>We assessed associations between body mass index and airway eosinophilia as well as leptin and eotaxin production in 82 participants with asthma, 37 of whom exhibited obesity. Cultured human airway fibroblasts and mouse models of chronic allergic airway disease were used to evaluate leptin’s effect on eotaxin production and lung eosinophilia. The role of IL-13 receptor alpha 2 (IL-13Rα2) in mediating these processes was examined using specific neutralizing antibodies <em>in vitro</em>.</div></div><div><h3>Results</h3><div>In participants with T2 asthma and obesity, we observed that airway tissue eosinophilia did not associate with traditional T2 inflammation metrics such as peripheral and/or bronchoalveolar lavage fluid eosinophil counts or with fractional exhaled nitric oxide. Alternatively, we observed elevated bronchoalveolar lavage fluid leptin and eotaxin-1 levels. In airway fibroblasts from participants with asthma, leptin augmented IL-13–induced eotaxin-1 and eotaxin-3 production and <em>IL13RA2</em> expression. In mice, elevated leptin promoted airway IL-13Rα2 and eotaxin production by lung fibroblasts and lung tissue eosinophilia following chronic house dust mite allergen exposure. Inhibition of IL-13Rα2 reduced combined leptin and IL-13–stimulated eotaxin secretion by human airway fibroblasts.</div></div><div><h3>Conclusions</h3><div>We identified a potential association explaining airway tissue eosinophil retention in obesity-associated T2 asthma through leptin-mediated enhancement of IL-13–induced eosinophil chemokine production by airway fibroblasts, a process requiring IL-13Rα2.</div></div>","PeriodicalId":14936,"journal":{"name":"Journal of Allergy and Clinical Immunology","volume":"155 3","pages":"Pages 819-833.e10"},"PeriodicalIF":11.4,"publicationDate":"2025-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142710263","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":"Somatic mosaicism in genetic errors of immunity","authors":"Megan A. Cooper MD, PhD","doi":"10.1016/j.jaci.2024.11.038","DOIUrl":"10.1016/j.jaci.2024.11.038","url":null,"abstract":"<div><div>Genetic mosaicism in somatic cells can lead to the presence of pathogenic variants in a subset of immune cells causing genetic errors of immunity, often phenocopying germline inborn errors of immunity. Over the last 2 decades, significant progress has been made in the identification of these disorders in patients, including discovery of new diseases. Diagnosis of disease-causing somatic mosaicism provides a target for treatment and monitoring of patients and has implications for genetic counseling. However, there continue to be barriers in the identification of somatic mosaicism, particularly for the clinical diagnosis of patients, based on the limitations of current diagnostic sequencing and analysis approaches. This review focuses on how somatic mosaicism can lead to genetic errors of immunity, the genes known to be associated with somatic genetic errors of immunity, and challenges in the field for accurate diagnosis of patients.</div></div>","PeriodicalId":14936,"journal":{"name":"Journal of Allergy and Clinical Immunology","volume":"155 3","pages":"Pages 759-767"},"PeriodicalIF":11.4,"publicationDate":"2025-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142887520","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":"Novel applications of large language models in clinical research","authors":"Michael S. Abers MD ,&nbsp;Rasika A. Mathias ScD","doi":"10.1016/j.jaci.2024.12.1088","DOIUrl":"10.1016/j.jaci.2024.12.1088","url":null,"abstract":"","PeriodicalId":14936,"journal":{"name":"Journal of Allergy and Clinical Immunology","volume":"155 3","pages":"Pages 813-814"},"PeriodicalIF":11.4,"publicationDate":"2025-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143023412","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":"News beyond our pages - March 2025","authors":"","doi":"10.1016/j.jaci.2025.01.010","DOIUrl":"10.1016/j.jaci.2025.01.010","url":null,"abstract":"","PeriodicalId":14936,"journal":{"name":"Journal of Allergy and Clinical Immunology","volume":"155 3","pages":"Pages 798-799"},"PeriodicalIF":11.4,"publicationDate":"2025-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143519488","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":"Lung function trajectories in common variable immunodeficiencies: An observational retrospective multicenter study","authors":"Helena Buso MD ,&nbsp;Davide Firinu MD ,&nbsp;Renato Finco Gambier MD ,&nbsp;Riccardo Scarpa MD, PhD ,&nbsp;Giulia Garzi MD ,&nbsp;Valentina Soccodato MD ,&nbsp;Giulia Costanzo MD ,&nbsp;Andrea G. Ledda MD ,&nbsp;Nicolò Rashidy MD ,&nbsp;Ilaria Bertozzi MD ,&nbsp;Stefania Nicola MD ,&nbsp;Giulio Tessarin MD ,&nbsp;Mauro Ramigni MD ,&nbsp;Cinzia Piovesan MSc ,&nbsp;Fabrizio Vianello MD ,&nbsp;Andrea Vianello MD ,&nbsp;Stefano Del Giacco MD ,&nbsp;Vassilios Lougaris MD ,&nbsp;Luisa Brussino MD ,&nbsp;Mark G. Jones MD, PhD ,&nbsp;Francesco Cinetto MD, PhD","doi":"10.1016/j.jaci.2024.10.037","DOIUrl":"10.1016/j.jaci.2024.10.037","url":null,"abstract":"<div><h3>Background</h3><div>Respiratory disease is a frequent cause of morbidity and mortality in common variable immunodeficiencies (CVIDs); however, lung function trajectories are poorly understood.</div></div><div><h3>Objective</h3><div>We sought to determine lung physiology measurements in CVIDs, their temporal trajectory, and their association with clinical and immunologic parameters.</div></div><div><h3>Methods</h3><div>This retrospective study from 5 Italian centers included patients with CVIDs who had longitudinal pulmonary function tests (PFTs) and chest computed tomography scan available. Applying the European Respiratory Society/American Thoracic Society 2021 standard, PFTs were expressed as percentile value within the normal distribution of healthy individuals, with the 5th percentile identified as lower limit of normal (LLN). The association of lung function with clinical and immunologic parameters was investigated.</div></div><div><h3>Results</h3><div>The study included 185 patients with CVIDs; 64% had at least 1 lung comorbidity (bronchiectasis: 41%; granulomatous interstitial lung diseases: 24%). At first spirometry, median FEV₁ was 3.07 L (interquartile range: 2.40-3.80 L), at the 32nd percentile (6th-61st percentile), and median forced vital capacity (FVC) was 3.70 L (interquartile range: 3.00-.54 L), at the 29th percentile (7th-49th percentile). Of patients, 23% had FEV₁ &lt; LLN, and 21% had FVC &lt; LLN. Switched-memory B cells &lt;2% were associated with both FEV₁ &lt; LLN (odds ratio 7.58) and FVC &lt; LLN (odds ratio 3.55). In 112 patients with at least 5 years of PFTs, we found no significant difference between measured and predicted annual decline of FEV₁ (25.6 mL/year vs 20.7 mL/year) and FVC (15.6 mL/year vs 16.2 mL/year).</div></div><div><h3>Conclusions</h3><div>In our study, lung volumes of the majority of patients with CVIDs were in the lower third of normal distribution of healthy individuals. After diagnosis, rate of lung decline was not accelerated.</div></div>","PeriodicalId":14936,"journal":{"name":"Journal of Allergy and Clinical Immunology","volume":"155 3","pages":"Pages 1027-1035"},"PeriodicalIF":11.4,"publicationDate":"2025-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142681824","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":"Aspergillus-mediated allergic airway inflammation is triggered by dendritic cell recognition of a defined spore morphotype","authors":"Emma L. Houlder PhD ,&nbsp;Sara Gago PhD ,&nbsp;George Vere PhD ,&nbsp;Julio Furlong-Silva PhD ,&nbsp;Daniel Conn MSc ,&nbsp;Emer Hickey PhD ,&nbsp;Saba Khan MSc ,&nbsp;Darren Thomson PhD ,&nbsp;Mark W. Shepherd MSc ,&nbsp;Ressa Lebedinec PhD ,&nbsp;Gordon D. Brown PhD ,&nbsp;William Horsnell PhD ,&nbsp;Mike Bromley PhD ,&nbsp;Andrew S. MacDonald PhD ,&nbsp;Peter C. Cook PhD","doi":"10.1016/j.jaci.2024.10.040","DOIUrl":"10.1016/j.jaci.2024.10.040","url":null,"abstract":"<div><h3>Background</h3><div>Exposure to fungi, especially <em>Aspergillus fumigatus,</em> can elicit potent allergic inflammation that triggers and worsens asthmatic disease. Dendritic cells (DCs) initiate allergic inflammatory responses to allergic stimuli. However, it is unclear if <em>Af</em> spores during isotropic growth (early spore swelling) can activate DCs to initiate allergic responses or if germination is required. This lack of basic understanding of how <em>Af</em> causes disease is a barrier to developing new treatments.</div></div><div><h3>Objective</h3><div>We sought to show that a precise <em>Af</em> morphotype stage during spore swelling can trigger DCs to mediate allergic inflammatory responses and ascertain if antifungal therapeutics can be effective at suppressing this process.</div></div><div><h3>Methods</h3><div>We used an <em>Af</em> strain deficient in pyrimidine biosynthesis <em>(ΔpyrG)</em> to generate populations of <em>Af</em> spores arrested at different stages of isotropic growth (swelling) via temporal removal of uracil and uridine from growth media. These arrested spore stages were cultured with bone marrow–derived DCs (BMDCs), and their activation was measured via flow cytometry and ELISA to examine which growth stage was able to activate BMDCs. These BMDCs were then adoptively transferred into the airways to assess if they were able to mediate allergic inflammation in naïve recipient mice. Allergic airway inflammation <em>in vivo</em> was determined via flow cytometry, ELISA, and real-time quantitative PCR. This system was also used to determine if antifungal drug (itraconazole) treatment could alter early stages of spore swelling and therefore BMDC activation and <em>in vivo</em> allergic inflammation upon adoptive transfer.</div></div><div><h3>Results</h3><div>We found that <em>Af</em> isotropic growth is essential to trigger BMDC activation and mediate allergic airway inflammation. Furthermore, using time-arrested <em>Af</em> stages, we found that at least 3 hours in growth media enabled spores to swell sufficiently to activate BMDCs to elicit allergic airway inflammation <em>in vivo.</em> Incubation of germinating <em>Af</em> with itraconazole reduced spore swelling and partially reduced their ability to activate BMDCs to elicit <em>in vivo</em> allergic airway inflammation.</div></div><div><h3>Conclusion</h3><div>Our results have pinpointed the precise stage of <em>Af</em> development when germinating spores are able to activate DCs to mediate downstream allergic airway inflammation. Furthermore, we have identified that antifungal therapeutics partially reduced the potential of <em>Af</em> spores to stimulate allergic responses, highlighting a potential mechanism by which antifungal treatment might help prevent the development of fungal allergy.</div></div>","PeriodicalId":14936,"journal":{"name":"Journal of Allergy and Clinical Immunology","volume":"155 3","pages":"Pages 988-1001"},"PeriodicalIF":11.4,"publicationDate":"2025-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142710251","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":"Clinical response and corresponding blood transcriptome pathways before and after treatment of hereditary angioedema prodromes compared to active swelling attacks","authors":"Debajyoti Ghosh PhD ,&nbsp;John Anderson MD ,&nbsp;Umesh Singh MD, PhD ,&nbsp;Cheryl K. Bernstein RN, BSN, CCRC ,&nbsp;Jonathan A. Bernstein MD","doi":"10.1016/j.jaci.2024.11.035","DOIUrl":"10.1016/j.jaci.2024.11.035","url":null,"abstract":"<div><h3>Background</h3><div>Approximately 85% of hereditary angioedema (HAE) attacks are associated with prodromal symptoms.</div></div><div><h3>Objective</h3><div>We investigated the clinical effect of treating HAE C1-esterase inhibitor (HAE-C1-INH) type 1 patients with recombinant human C1-INH (rhC1-INH) during their prodrome versus an active swelling episode and associated changes in blood transcriptomic genes and pathways before and after treatment.</div></div><div><h3>Methods</h3><div>A 2-center, unblinded, case-crossover study randomly assigned 5 HAE-C1-INH type 1 patients to prodrome or attack treatment groups; after a patient was treated for either 2 prodromes or 2 HAE attacks, they were crossed over to be treated for 2 HAE attacks or 2 prodromes. All patients were treated during the prodrome or acute attack with rhC1-INH; (conestat alfa, 50 IU/kg body weight, maximum 4200 IU for body weight ≥85 kg). Blood samples for analysis by RNA sequencing were obtained (1) at baseline, (2) during the prodrome before and after treatment, and (3) during an attack before and after treatment. Differentially expressed genes and pathways were elucidated by Ingenuity Pathway Analysis (IPA; Qiagen).</div></div><div><h3>Results</h3><div>Treatment during the HAE prodrome with rhC1-INH was as effective at preventing progression to a swelling episode as treatment of an acute attack. HAE prodromes were associated with upregulation of multiple inflammatory extracellular matrix genes, neuropeptide, and inflammasome member genes (eg, <em>SPARCL1, AGRP, NLRP9;</em> log₂ fold change = 4.1, 3.9, and 3.0, respectively). TNF-α and IL-10 were 2 major hub genes in prodrome-associated enriched gene networks. rhC1-INH treatment resulted in reversal of the disease signature in HAE-associated dysregulated pathways. Approximately 42% of prodrome-associated differentially expressed genes were also associated with HAE attacks. The enriched gene networks with hub genes for prodrome (<em>ERK</em> and <em>VEGF</em>) and for acute attack (insulin and <em>SERPINA1</em>) stages of HAE were identified. The major enriched pathways shared between HAE prodrome and attack were associated with neutrophil function and prostaglandin metabolism.</div></div><div><h3>Conclusion</h3><div>Treatment of HAE-C1-INH type 1 patients who have a well-defined prodrome that historically results in an acute attack may be justified clinically and mechanistically. This approach would represent a paradigm shift for management of HAE on-demand treatment.</div></div>","PeriodicalId":14936,"journal":{"name":"Journal of Allergy and Clinical Immunology","volume":"155 3","pages":"Pages 947-955"},"PeriodicalIF":11.4,"publicationDate":"2025-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142828271","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}