Kyle T. Mincham, Lola E. Loewenthal, Garance F. M. Meyer, Sara Fontanella, Martina Marfia, Minerva Garcia Martin, Viola Kaygusuz, Charlotte Goss, Simone A. Walker, Franz Puttur, Andrew Menzies-Gow, Pujan Patel, Clare M. Lloyd, Robert J. Snelgrove
{"title":"严重哮喘的特征是性别特异性的ILC景观和异常的气道特征,抗il -5/ 5r α生物制剂可抑制这些特征","authors":"Kyle T. Mincham, Lola E. Loewenthal, Garance F. M. Meyer, Sara Fontanella, Martina Marfia, Minerva Garcia Martin, Viola Kaygusuz, Charlotte Goss, Simone A. Walker, Franz Puttur, Andrew Menzies-Gow, Pujan Patel, Clare M. Lloyd, Robert J. Snelgrove","doi":"10.1126/scitranslmed.adu4913","DOIUrl":null,"url":null,"abstract":"<div >Innate lymphoid cells (ILCs) fulfill critical roles in maintenance of tissue-specific homeostasis but have also been implicated in disease pathology when dysregulated. Although they are broadly classified into three core subsets, it is increasingly apparent that ILCs exhibit plasticity in response to microenvironmental factors. Accurate and holistic evaluation of the ILC landscape is critical to understanding the contribution of ILCs to disease pathology. Using high-parameter flow cytometry, we comprehensively interrogated the phenotypic and functional diversity of ILCs in healthy volunteers and patients with severe asthma (SA), assessing the reciprocity between peripheral blood and airway compartments and dissecting the impact of anti–IL-5/5Rα biologics on these responses. We identified substantial heterogeneity and putative plasticity in human ILC responses, highlighting inherent limitations of conventional enumeration strategies. Deep phenotypic and functional profiling demonstrated a distinct sexual dimorphism in ILC responses in patients with SA. Females displayed an elevated abundance of circulating ILC progenitors, ILC1s, and ILC3s, whereas males presented with diminished ILC2s compared with respective healthy controls. Circulating ILC progenitors inversely correlated with testosterone concentrations. Moreover, we identified a reciprocal influx of all core ILC subsets into the airways of patients with SA, with unbiased multisource clustering identifying a relationship between elevated airway ILC2s and reduced lung function. Last, we showed that anti–IL-5/5Rα biologics largely ablated airway ILC type 2 cytokine production without affecting core ILC subset abundance in the peripheral blood or airways, identifying a potential mechanism whereby anti–IL-5/5Rα biologics alleviate clinical disease in patients with SA.</div>","PeriodicalId":21580,"journal":{"name":"Science Translational Medicine","volume":"17 818","pages":""},"PeriodicalIF":14.6000,"publicationDate":"2025-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.science.org/doi/reader/10.1126/scitranslmed.adu4913","citationCount":"0","resultStr":"{\"title\":\"Severe asthma is characterized by a sex-specific ILC landscape and aberrant airway profile that is suppressed by anti–IL-5/5Rα biologics\",\"authors\":\"Kyle T. Mincham, Lola E. Loewenthal, Garance F. M. Meyer, Sara Fontanella, Martina Marfia, Minerva Garcia Martin, Viola Kaygusuz, Charlotte Goss, Simone A. 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We identified substantial heterogeneity and putative plasticity in human ILC responses, highlighting inherent limitations of conventional enumeration strategies. Deep phenotypic and functional profiling demonstrated a distinct sexual dimorphism in ILC responses in patients with SA. Females displayed an elevated abundance of circulating ILC progenitors, ILC1s, and ILC3s, whereas males presented with diminished ILC2s compared with respective healthy controls. Circulating ILC progenitors inversely correlated with testosterone concentrations. Moreover, we identified a reciprocal influx of all core ILC subsets into the airways of patients with SA, with unbiased multisource clustering identifying a relationship between elevated airway ILC2s and reduced lung function. 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Severe asthma is characterized by a sex-specific ILC landscape and aberrant airway profile that is suppressed by anti–IL-5/5Rα biologics
Innate lymphoid cells (ILCs) fulfill critical roles in maintenance of tissue-specific homeostasis but have also been implicated in disease pathology when dysregulated. Although they are broadly classified into three core subsets, it is increasingly apparent that ILCs exhibit plasticity in response to microenvironmental factors. Accurate and holistic evaluation of the ILC landscape is critical to understanding the contribution of ILCs to disease pathology. Using high-parameter flow cytometry, we comprehensively interrogated the phenotypic and functional diversity of ILCs in healthy volunteers and patients with severe asthma (SA), assessing the reciprocity between peripheral blood and airway compartments and dissecting the impact of anti–IL-5/5Rα biologics on these responses. We identified substantial heterogeneity and putative plasticity in human ILC responses, highlighting inherent limitations of conventional enumeration strategies. Deep phenotypic and functional profiling demonstrated a distinct sexual dimorphism in ILC responses in patients with SA. Females displayed an elevated abundance of circulating ILC progenitors, ILC1s, and ILC3s, whereas males presented with diminished ILC2s compared with respective healthy controls. Circulating ILC progenitors inversely correlated with testosterone concentrations. Moreover, we identified a reciprocal influx of all core ILC subsets into the airways of patients with SA, with unbiased multisource clustering identifying a relationship between elevated airway ILC2s and reduced lung function. Last, we showed that anti–IL-5/5Rα biologics largely ablated airway ILC type 2 cytokine production without affecting core ILC subset abundance in the peripheral blood or airways, identifying a potential mechanism whereby anti–IL-5/5Rα biologics alleviate clinical disease in patients with SA.
期刊介绍:
Science Translational Medicine is an online journal that focuses on publishing research at the intersection of science, engineering, and medicine. The goal of the journal is to promote human health by providing a platform for researchers from various disciplines to communicate their latest advancements in biomedical, translational, and clinical research.
The journal aims to address the slow translation of scientific knowledge into effective treatments and health measures. It publishes articles that fill the knowledge gaps between preclinical research and medical applications, with a focus on accelerating the translation of knowledge into new ways of preventing, diagnosing, and treating human diseases.
The scope of Science Translational Medicine includes various areas such as cardiovascular disease, immunology/vaccines, metabolism/diabetes/obesity, neuroscience/neurology/psychiatry, cancer, infectious diseases, policy, behavior, bioengineering, chemical genomics/drug discovery, imaging, applied physical sciences, medical nanotechnology, drug delivery, biomarkers, gene therapy/regenerative medicine, toxicology and pharmacokinetics, data mining, cell culture, animal and human studies, medical informatics, and other interdisciplinary approaches to medicine.
The target audience of the journal includes researchers and management in academia, government, and the biotechnology and pharmaceutical industries. It is also relevant to physician scientists, regulators, policy makers, investors, business developers, and funding agencies.