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The enigmatic eosinophil has emerged as an exciting component of the immune system, involved in a plethora of homeostatic and inflammatory responses. Substantial progress has been achieved through experimental systems manipulating eosinophils in vivo, initially in mice and more recently in humans. Researchers using eosinophil knockout mice have identified a contributory role for eosinophils in basal and inflammatory processes and protective immunity. Primarily fueled by the purported proinflammatory role of eosinophils in eosinophil-associated diseases, a series of anti-eosinophil therapeutics have emerged as a new class of drugs. These agents, which dramatically deplete eosinophils, provide a valuable opportunity to characterize the consequences of eosinophil knockout humans. Herein, we comparatively describe mouse and human eosinophil knockouts. We put forth the view that human eosinophils negatively contribute to a variety of diseases and, unlike mouse eosinophils, do not yet have an identified role in physiological health; thus, clarifying all roles of eosinophils remains an ongoing pursuit.
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Eosinófilos , Preparaciones Farmacéuticas , Animales , Terapia Biológica , Humanos , Ratones , Ratones NoqueadosRESUMEN
The activities, ontogeny, and mechanisms of lineage expansion of eosinophils are less well resolved than those of other immune cells, despite the use of biological therapies targeting the eosinophilia-promoting cytokine interleukin (IL)-5 or its receptor, IL-5Rα. We combined single-cell proteomics and transcriptomics and generated transgenic IL-5Rα reporter mice to revisit eosinophilopoiesis. We reconciled human and murine eosinophilopoiesis and provided extensive cell-surface immunophenotyping and transcriptomes at different stages along the continuum of eosinophil maturation. We used these resources to show that IL-5 promoted eosinophil-lineage expansion via transit amplification, while its deletion or neutralization did not compromise eosinophil maturation. Informed from our resources, we also showed that interferon response factor-8, considered an essential promoter of myelopoiesis, was not intrinsically required for eosinophilopoiesis. This work hence provides resources, methods, and insights for understanding eosinophil ontogeny, the effects of current precision therapeutics, and the regulation of eosinophil development and numbers in health and disease.
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Linaje de la Célula , Eosinófilos , Interleucina-5 , Ratones Transgénicos , Proteómica , Análisis de la Célula Individual , Transcriptoma , Eosinófilos/inmunología , Eosinófilos/metabolismo , Animales , Interleucina-5/metabolismo , Interleucina-5/genética , Humanos , Ratones , Proteómica/métodos , Análisis de la Célula Individual/métodos , Diferenciación Celular/inmunología , Ratones Endogámicos C57BL , Perfilación de la Expresión Génica/métodos , Subunidad alfa del Receptor de Interleucina-5/metabolismo , Subunidad alfa del Receptor de Interleucina-5/genética , Mielopoyesis/genética , Factores Reguladores del Interferón/metabolismo , Factores Reguladores del Interferón/genética , Ratones NoqueadosRESUMEN
Cytokines regulate immune responses by binding to cell surface receptors, including the common subunit beta (ßc), which mediates signaling for GM-CSF, IL-3, and IL-5. Despite known roles in inflammation, the structural basis of IL-5 receptor activation remains unclear. We present the cryo-EM structure of the human IL-5 ternary receptor complex, revealing architectural principles for IL-5, GM-CSF, and IL-3. In mammalian cell culture, single-molecule imaging confirms hexameric IL-5 complex formation on cell surfaces. Engineered chimeric receptors show that IL-5 signaling, as well as IL-3 and GM-CSF, can occur through receptor heterodimerization, obviating the need for higher-order assemblies of ßc dimers. These findings provide insights into IL-5 and ßc receptor family signaling mechanisms, aiding in the development of therapies for diseases involving deranged ßc signaling.
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Microscopía por Crioelectrón , Factor Estimulante de Colonias de Granulocitos y Macrófagos , Interleucina-3 , Multimerización de Proteína , Receptores de Interleucina-5 , Transducción de Señal , Humanos , Sitios de Unión , Subunidad beta Común de los Receptores de Citocinas/metabolismo , Subunidad beta Común de los Receptores de Citocinas/genética , Subunidad beta Común de los Receptores de Citocinas/química , Factor Estimulante de Colonias de Granulocitos y Macrófagos/metabolismo , Factor Estimulante de Colonias de Granulocitos y Macrófagos/química , Factor Estimulante de Colonias de Granulocitos y Macrófagos/genética , Células HEK293 , Interleucina-3/metabolismo , Interleucina-3/química , Interleucina-3/genética , Interleucina-5/metabolismo , Modelos Moleculares , Unión Proteica , Receptores de Interleucina-5/metabolismo , Receptores de Interleucina-5/genética , Receptores de Interleucina-5/química , Imagen Individual de Molécula , Relación Estructura-ActividadRESUMEN
The perinatal period is a critical window for distribution of innate tissue-resident immune cells within developing organs. Despite epidemiologic evidence implicating the early-life environment in the risk for allergy, temporally controlled lineage tracing of group 2 innate lymphoid cells (ILC2s) during this period remains unstudied. Using complementary fate-mapping approaches and reporters for ILC2 activation, we show that ILC2s appeared in multiple organs during late gestation like tissue macrophages, but, unlike the latter, a majority of peripheral ILC2 pools were generated de novo during the postnatal window. This period was accompanied by systemic ILC2 priming and acquisition of tissue-specific transcriptomes. Although perinatal ILC2s were variably replaced across tissues with age, the dramatic increases in tissue ILC2s following helminth infection were mediated through local expansion independent of de novo generation by bone marrow hematopoiesis. We provide comprehensive temporally controlled fate mapping of an innate lymphocyte subset with notable nuances as compared to tissue macrophage ontogeny.
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Inmunidad Innata , Activación de Linfocitos/inmunología , Subgrupos Linfocitarios/inmunología , Subgrupos Linfocitarios/metabolismo , Animales , Femenino , Marcación de Gen , Ratones , Ratones Transgénicos , Especificidad de Órganos/inmunología , Embarazo , Sitios de Carácter Cuantitativo , Receptores de Interleucina-7/metabolismo , Transducción de SeñalRESUMEN
The ß common chain cytokines GM-CSF, IL-3, and IL-5 regulate varied inflammatory responses that promote the rapid clearance of pathogens but also contribute to pathology in chronic inflammation. Therapeutic interventions manipulating these cytokines are approved for use in some cancers as well as allergic and autoimmune disease, and others show promising early clinical activity. These approaches are based on our understanding of the inflammatory roles of these cytokines; however, GM-CSF also participates in the resolution of inflammation, and IL-3 and IL-5 may also have such properties. Here, we review the functions of the ß common cytokines in health and disease. We discuss preclinical and clinical data, highlighting the potential inherent in targeting these cytokine pathways, the limitations, and the important gaps in understanding of the basic biology of this cytokine family.
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Factor Estimulante de Colonias de Granulocitos y Macrófagos/inmunología , Inflamación/inmunología , Interleucina-3/inmunología , Interleucina-5/inmunología , Animales , Enfermedades Autoinmunes/inmunología , Factor Estimulante de Colonias de Granulocitos y Macrófagos/deficiencia , Factor Estimulante de Colonias de Granulocitos y Macrófagos/genética , Factor Estimulante de Colonias de Granulocitos y Macrófagos/uso terapéutico , Hematopoyesis/inmunología , Humanos , Inflamación/terapia , Interleucina-3/antagonistas & inhibidores , Interleucina-3/deficiencia , Interleucina-3/genética , Interleucina-5/antagonistas & inhibidores , Interleucina-5/deficiencia , Interleucina-5/genética , Ratones , Ratones Noqueados , Familia de Multigenes , Neoplasias/inmunología , Neoplasias/terapia , Receptores de Factor Estimulante de Colonias de Granulocitos y Macrófagos/genética , Receptores de Factor Estimulante de Colonias de Granulocitos y Macrófagos/inmunología , Receptores de Interleucina-3/genética , Receptores de Interleucina-3/inmunología , Receptores de Interleucina-5/genética , Receptores de Interleucina-5/inmunología , Proteínas Recombinantes/inmunología , Proteínas Recombinantes/uso terapéutico , Transducción de Señal , Relación Estructura-Actividad , Vacunación , Cicatrización de Heridas/inmunologíaRESUMEN
B cell initial activity is regulated through a balance of activation and suppression mediated by regulatory molecules expressed in B cells; however, the molecular mechanisms underlying this process remain incompletely understood. In this study, we investigated the function of the Fc receptor-like (Fcrl) family molecule Fcrl5, which is constitutively expressed on naïve B cells, in humoral immune responses. Our study demonstrated that B cell-specific overexpression of Fcrl5 enhanced antibody (Ab) production in both T cell-independent type 1 (TI1) and T cell-dependent (TD) responses. Additionally, it promoted effector B cell formation under competitive conditions in TD responses. Mechanistically, in vitro ligation of Fcrl5 by agonistic Abs reduced cell death and enhanced proliferation in lipopolysaccharide (LPS)-stimulated B cells. In the presence of anti-CD40 Abs and IL-5, the Fcrl5 ligation not only suppressed cell death but also enhanced differentiation into plasma cells. These findings reveal a novel role of Fcrl5 in promoting humoral immune responses by enhancing B cell viability and plasma cell differentiation.
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RATIONALE: There is no consensus on criteria to include in an asthma remission definition in real-life. Factors associated with achieving remission post-biologic-initiation remain poorly understood. OBJECTIVES: To quantify the proportion of adults with severe asthma achieving multi-domain-defined remission post-biologic-initiation and identify pre-biologic characteristics associated with achieving remission which may be used to predict it. METHODS: This was a longitudinal cohort study using data from 23 countries from the International Severe Asthma Registry. Four asthma outcome domains were assessed in the 1-year pre- and post-biologic-initiation. A priori-defined remission cut-offs were: 0 exacerbations/year, no long-term oral corticosteroid (LTOCS), partly/well-controlled asthma, and percent predicted forced expiratory volume in one second ≥80%. Remission was defined using 2 (exacerbations + LTOCS), 3 (+control or +lung function) and 4 of these domains. The association between pre-biologic characteristics and post-biologic remission was assessed by multivariable analysis. MEASUREMENTS AND MAIN RESULTS: 50.2%, 33.5%, 25.8% and 20.3% of patients met criteria for 2, 3 (+control), 3 (+lung function) and 4-domain-remission, respectively. The odds of achieving 4-domain remission decreased by 15% for every additional 10-years asthma duration (odds ratio: 0.85; 95% CI: 0.73, 1.00). The odds of remission increased in those with fewer exacerbations/year, lower LTOCS daily dose, better control and better lung function pre-biologic-initiation. CONCLUSIONS: One in 5 patients achieved 4-domain remission within 1-year of biologic-initiation. Patients with less severe impairment and shorter asthma duration at initiation had a greater chance of achieving remission post-biologic, indicating that biologic treatment should not be delayed if remission is the goal. This article is open access and distributed under the terms of the Creative Commons Attribution Non-Commercial No Derivatives License 4.0 (http://creativecommons.org/licenses/by-nc-nd/4.0/).
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BACKGROUND: Episodic angioedema with eosinophilia (EAE) is a rare multilineage cyclic syndrome of unknown etiology characterized by episodes of angioedema, myalgia, fatigue, and fever that occur every 3 to 8 weeks and resolve between episodes without therapy. Cyclic elevations in serum IL-5 levels and neutrophils precede the increase in absolute eosinophil count (AEC) in most patients. OBJECTIVE: We sought to assess the role of IL-5-driven eosinophilia in the clinical manifestations of EAE. METHODS: An open-label pilot study of mepolizumab (700 mg intravenously monthly for 3 months followed by sequential dose reduction to the Food and Drug Administration-approved dose of 300 mg subcutaneously monthly) was conducted. The primary end point was reduction in the number and severity of clinical symptoms as assessed by patient-reported symptom questionnaires. Secondary end points were greater than or equal to 75% reduction in peak AEC after 1 dose of mepolizumab and sustained reduction in AEC after 3 doses of mepolizumab. Exploratory end points included effects of mepolizumab treatment on other cell lineages (numbers and surface marker expression), levels of plasma mediators, and biomarkers of eosinophil activation. RESULTS: Four female and 1 male (median age, 45 years) participants with EAE were enrolled. None of the 5 participants experienced a reduction in the number of symptomatic flares on mepolizumab therapy, and 1 participant withdrew before study completion because of lack of improvement. Peak AEC was reduced by 75% or more in 3 participants after the first dose of mepolizumab and in 4 participants after 3 doses. CONCLUSIONS: In a small cohort of participants with EAE, mepolizumab was unsuccessful in substantially reducing clinical symptoms despite reduction in AEC.
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Angioedema , Anticuerpos Monoclonales Humanizados , Eosinofilia , Humanos , Masculino , Femenino , Persona de Mediana Edad , Proyectos Piloto , Interleucina-5 , Eosinofilia/tratamiento farmacológico , EosinófilosRESUMEN
BACKGROUND: Chronic rhinosinusitis with nasal polyps (CRSwNP) causes nasal obstruction and olfactory dysfunction. Aspirin-exacerbated respiratory disease (AERD) is the triad of CRSwNP, asthma, and respiratory reactions to COX-1 inhibitors. Patients with AERD have elevated nasal IL-5 levels and high numbers of antibody-secreting cells (ASCs), including plasma cells and plasmablasts, in their polyp tissue; in addition, their nasal polyp (NP) IgE levels are correlated with disease severity and recurrence of nasal polyposis. OBJECTIVE: We sought to explore differences in the transcriptomic profile, activation markers, and IL-5Rα expression and function of NP ASCs from patients with AERD and CRSwNP. METHODS: NP tissue was collected from patients with AERD and CRSwNP and digested into single-cell suspensions. NP cells were analyzed for protein expression by mass cytometry. For IL-5Rα functional studies, plasma cells were purified and cultured in vitro with or without IL-5 and analyzed by bulk RNA sequencing. RESULTS: Compared with polyp tissue from patients with CRSwNP, polyp tissue from patients with AERD contained significantly more ASCs and had increased ASC expression of IL-5Rα. ASCs from patients with AERD expressed higher protein levels of B-cell activation and regulatory markers (CD40, CD19, CD32, and CD38) and the proliferation marker Ki-67. ASCs from patients with AERD also expressed more IL5RA, IGHE, and cell cycle- and proliferation-related transcripts (CCND2, MKI67, CDC25A, and CDC25B) than did ASCs from patients with CRSwNP. Stimulation of plasma cells from patients with AERD with IL-5 induced key cell cycle genes (CCND2 and PTP4A3), whereas IL-5 stimulation of ASCs from patients with CRSwNP induced few transcriptomic changes. CONCLUSION: NP tissue ASCs from patients with AERD express higher levels of functional IL-5Rα and markers associated with cell cycling and proliferation than do ASCs from patients with aspirin-tolerant CRSwNP.
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Asma Inducida por Aspirina , Pólipos Nasales , Rinitis , Sinusitis , Humanos , Pólipos Nasales/metabolismo , Interleucina-5 , Rinitis/metabolismo , Asma Inducida por Aspirina/metabolismo , Aspirina/efectos adversos , Enfermedad Crónica , Células Productoras de Anticuerpos/metabolismo , Sinusitis/metabolismo , Proliferación Celular , Proteínas de Neoplasias , Proteínas Tirosina FosfatasasRESUMEN
BACKGROUND: Nonneuronal cells, including epithelial cells, can produce acetylcholine (ACh). Muscarinic ACh receptor antagonists are used clinically to treat asthma and other medical conditions; however, knowledge regarding the roles of ACh in type 2 immunity is limited. OBJECTIVE: Our aim was to investigate the roles of epithelial ACh in allergic immune responses. METHODS: Human bronchial epithelial (HBE) cells were cultured with allergen extracts, and their ACh production and IL-33 secretion were studied in vitro. To investigate immune responses in vivo, naive BALB/c mice were treated intranasally with different muscarinic ACh receptor antagonists and then exposed intranasally to allergens. RESULTS: At steady state, HBE cells expressed cellular components necessary for ACh production, including choline acetyltransferase and organic cation transporters. Exposure to allergens caused HBE cells to rapidly release ACh into the extracellular medium. Pharmacologic or small-interfering RNA-based blocking of ACh production or autocrine action through the M3 muscarinic ACh receptors in HBE cells suppressed allergen-induced ATP release, calcium mobilization, and extracellular secretion of IL-33. When naive mice were exposed to allergens, ACh was quickly released into the airway lumen. A series of clinical M3 muscarinic ACh receptor antagonists inhibited allergen-induced IL-33 secretion and innate type 2 immune response in the mouse airways. In a preclinical murine model of asthma, an ACh receptor antagonist suppressed allergen-induced airway inflammation and airway hyperreactivity. CONCLUSIONS: ACh is released quickly by airway epithelial cells on allergen exposure, and it plays an important role in type 2 immunity. The epithelial ACh system can be considered a therapeutic target in allergic airway diseases.
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Asma , Interleucina-33 , Ratones , Animales , Humanos , Interleucina-33/metabolismo , Ratones Noqueados , Pulmón , Epitelio , Acetilcolina , Alérgenos , Colinérgicos , Receptores Colinérgicos/metabolismoRESUMEN
BACKGROUND: Patients with severe asthma can present with eosinophilic type 2 (T2), neutrophilic, or mixed inflammation that drives airway remodeling and exacerbations and represents a major treatment challenge. The common ß (ßc) receptor signals for 3 cytokines, GM-CSF, IL-5, and IL-3, which collectively mediate T2 and neutrophilic inflammation. OBJECTIVE: To determine the pathogenesis of ßc receptor-mediated inflammation and remodeling in severe asthma and to investigate ßc antagonism as a therapeutic strategy for mixed granulocytic airway disease. METHODS: ßc gene expression was analyzed in bronchial biopsy specimens from patients with mild-to-moderate and severe asthma. House dust mite extract and Aspergillus fumigatus extract (ASP) models were used to establish asthma-like pathology and airway remodeling in human ßc transgenic mice. Lung tissue gene expression was analyzed by RNA sequencing. The mAb CSL311 targeting the shared cytokine binding site of ßc was used to block ßc signaling. RESULTS: ßc gene expression was increased in patients with severe asthma. CSL311 potently reduced lung neutrophils, eosinophils, and interstitial macrophages and improved airway pathology and lung function in the acute steroid-resistant house dust mite extract model. Chronic intranasal ASP exposure induced airway inflammation and fibrosis and impaired lung function that was inhibited by CSL311. CSL311 normalized the ASP-induced fibrosis-associated extracellular matrix gene expression network and strongly reduced signatures of cellular inflammation in the lung. CONCLUSIONS: ßc cytokines drive steroid-resistant mixed myeloid cell airway inflammation and fibrosis. The anti-ßc antibody CSL311 effectively inhibits mixed T2/neutrophilic inflammation and severe asthma-like pathology and reverses fibrosis gene signatures induced by exposure to commonly encountered environmental allergens.
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Asma , Receptores de Citocinas , Ratones , Animales , Humanos , Receptores de Citocinas/metabolismo , Remodelación de las Vías Aéreas (Respiratorias) , Pulmón , Citocinas/metabolismo , Ratones Transgénicos , Inflamación , Alérgenos , Esteroides/uso terapéutico , Fibrosis , PyroglyphidaeRESUMEN
Cytolytic ETosis is a type of programmed cell death distinct from apoptosis and necrosis and plays a major role in the innate immune system and disease progression. Through the process of ETosis, cells release their chromatin with diverse antimicrobial proteins into the extracellular milieu, forming extracellular traps (ETs). Although ETosis has been reported in several leukocyte types, few studies have compared ETosis and the component proteins of ETs in leukocytes. The aim of this study was to better understand the characteristics of eosinophil ETosis (EETosis) compared with other leukocytes. We isolated human blood eosinophils, neutrophils, basophils, monocytes, and lymphocytes and stimulated them with known ETosis inducers, a protein kinase C activator PMA, or a calcium ionophore A23187. Both stimuli induced eosinophil cell death and ET release after 180 minutes of stimulation in a NADPH-oxidase-dependent manner. PMA also induced NADPH-oxidase-dependent ETosis in neutrophils, whereas little or no significant ETosis was observed in basophils, monocytes, or lymphocytes at 180 minutes. Mass spectrometry-based proteomic analysis of eosinophil- and neutrophil-derived ETs identified 997 and 1415 proteins, respectively. Among the physiological stimuli tested, immobilized IgA and IgG induced EETosis. C-C motif chemokine ligand 11 (CCL11) and interleukin 5 (IL-5) were weak inducers of EETosis, but co-stimulation significantly induced rapid EETosis. Under high serum or albumin conditions, co-stimulation with CCL11 and IL-5 paradoxically prolonged cell survival by preventing spontaneous apoptosis. This study provides an in-depth characterization of EETosis and highlights the precise regulation of eosinophil survival and cell death pathways.
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Asthma is a common and burdensome chronic inflammatory airway disease that affects both children and adults. One of the main concerns with asthma is the manifestation of irreversible tissue remodelling of the airways due to the chronic inflammatory environment that eventually disrupts the whole structure of the airways. Most people with troublesome asthma are treated with inhaled corticosteroids. However, the development of steroid resistance is a commonly encountered issue, necessitating other treatment options for these patients. Biological therapies are a promising therapeutic approach for people with steroid-resistant asthma. Interleukin 5 is recently gaining a lot of attention as a biological target relevant to the tissue remodelling process. Since IL-5-neutralizing monoclonal antibodies (mepolizumab, reslizumab and benralizumab) are currently available for clinical use, this review aims to revisit the role of IL-5 in asthma pathogenesis at large and airway remodelling in particular, in addition to exploring its role as a target for biological treatments.
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Remodelación de las Vías Aéreas (Respiratorias) , Asma , Interleucina-5 , Humanos , Asma/tratamiento farmacológico , Asma/inmunología , Asma/metabolismo , Remodelación de las Vías Aéreas (Respiratorias)/efectos de los fármacos , Interleucina-5/antagonistas & inhibidores , Interleucina-5/inmunología , Interleucina-5/metabolismo , Antiasmáticos/uso terapéutico , Antiasmáticos/farmacología , AnimalesRESUMEN
BACKGROUND: Cytokines are of utmost importance in both the physiological and pathological immune responses of the human body. This study utilized flow cytometry to measure the levels of plasma interleukin-2 (IL-2), interleukin-4 (IL-4), interleukin-5 (IL-5) and interleukin-17A (IL-17A) and established their reference intervals, aiming to provide data support for the diagnosis and treatment of clinical diseases. METHODS: According to the inclusion and exclusion criteria, a total of 728 reference individuals were included in this study from January 2023 to June 2023. The Kolmogorov-Smirnov test was used to analyse the distributions of plasma IL-2, IL-4, IL-5 and IL-17A. The reference intervals of plasma IL-2, IL-4, IL-5 and IL-17A were established by the unilateral percentile method (95th percentile) based on the guidelines of C28-A 3 and WS/T 402-2012. RESULTS: In this study, the levels of plasma IL-2, IL-4, IL-5 and IL-17A were nonnormally distributed. The concentrations of plasma IL-2, IL-4, IL-5 and IL-17A in healthy adults were not significantly different by sex or age (all P > 0.05). Therefore, all the reference individuals were combined into one group, and the reference intervals of plasma IL-2, IL-4, IL-5 and IL-17 were established by flow cytometry (IL-2 ≤ 10.25 pg/mL, IL-4 ≤ 9.87 pg/mL, IL-5 ≤ 3.36 pg/mL and IL-17A ≤ 9.46 pg/mL). CONCLUSIONS: We first established the reference intervals of plasma IL-2, IL-4, IL-5 and IL-17A in healthy adults based on a single-center population in the Jiangsu region in eastern China, which will provide an important reference value for evaluating human immune status and the diagnosis and treatment of clinical diseases.
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Citometría de Flujo , Interleucina-17 , Interleucina-2 , Interleucina-4 , Interleucina-5 , Humanos , Citometría de Flujo/métodos , Masculino , Interleucina-17/sangre , Femenino , Adulto , Interleucina-5/sangre , China , Interleucina-2/sangre , Interleucina-4/sangre , Persona de Mediana Edad , Valores de Referencia , Adulto Joven , Anciano , Voluntarios Sanos , AdolescenteRESUMEN
BACKGROUND: Atopic dermatitis (AD) is a chronic inflammatory skin disease resulting in decreased quality of life. Histamine and specifically the H4 receptor play a key role in the inflammatory process in AD and serve as targets for novel therapeutic approaches. OBJECTIVE: In the present study we aimed to elucidate the immunopathological mechanisms with which the H4 receptor impacts TH2 cells and contributes to AD pathophysiology. METHODS: Total CD4+ T cells obtained from healthy or AD individuals and in vitro differentiated TH2 cells were cultured under different conditions and the mRNA expression or protein production of target molecules were determined using quantitative real-time PCR and ELISA. RESULTS: H4 receptor mRNA expression was upregulated concentration dependent upon IL-4 stimulation in in vitro differentiated TH2 cells progressively during the differentiation. Transcriptomic analysis of in vitro differentiated TH2 versus TH1 cells revealed that the H4 receptor among other genes represents one of the highly upregulated genes in TH2 cells. Most importantly, increased amounts of IL-5 and IL-13 mRNA expression were detected in in vitro differentiated TH2 cells as well as protein secretion in the presence of histamine or of the H4 receptor-selective-agonist when compared to the untreated control. CONCLUSION: We show for the first time an H4 receptor dependent upregulation of the pro-inflammatory cytokines IL-5 and IL-13 in human TH2 cells by histamine. This suggests that the blockade of the H4 receptor may lead to downregulation of these cytokines and amelioration of AD symptoms as reported in first clinical studies.
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Dermatitis Atópica , Interleucina-13 , Interleucina-5 , Receptores Histamínicos H4 , Células Th2 , Humanos , Células Th2/inmunología , Células Th2/metabolismo , Dermatitis Atópica/inmunología , Dermatitis Atópica/metabolismo , Interleucina-13/metabolismo , Interleucina-5/metabolismo , Receptores Histamínicos H4/metabolismo , Diferenciación Celular/inmunología , Activación de Linfocitos/inmunología , Células CultivadasRESUMEN
Interleukin-7 (IL-7) is a cytokine critical for the development and maintenance of group 2 innate lymphoid cells (ILC2s). ILC2s are resident in peripheral tissues such as the intestine and lung. However, whether IL-7 produced in the lung plays a role in the maintenance and function of lung ILC2s during airway inflammation remains unknown. IL-7 was expressed in bronchoalveolar epithelial cells and lymphatic endothelial cells (LECs). To investigate the role of local IL-7 in lung ILC2s, we generated two types of IL-7 conditional knockout (IL-7cKO) mice: Sftpc-Cre (SPC-Cre) IL-7cKO mice specific for bronchial epithelial cells and type 2 alveolar epithelial cells and Lyve1-Cre IL-7cKO mice specific for LECs. In steady state, ILC2s were located near airway epithelia, although lung ILC2s were unchanged in the two lines of IL-7cKO mice. In papain-induced airway inflammation dependent on innate immunity, lung ILC2s localized near bronchia via CCR4 expression, and eosinophil infiltration and type 2 cytokine production were reduced in SPC-Cre IL-7cKO mice. In contrast, in house dust mite (HDM)-induced airway inflammation dependent on adaptive immunity, lung ILC2s localized near lymphatic vessels via their CCR2 expression 2 weeks after the last challenge. Furthermore, lung ILC2s were decreased in Lyve1-Cre IL-7cKO mice in the HDM-induced inflammation because of decreased cell survival and proliferation. Finally, administration of anti-IL-7 antibody attenuated papain-induced inflammation by suppressing the activation of ILC2s. Thus, this study demonstrates that IL-7 produced by bronchoalveolar epithelial cells and LECs differentially controls the activation and maintenance of lung ILC2s, where they are localized in airway inflammation.
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Inmunidad Innata , Interleucina-7 , Ratones , Animales , Células Endoteliales/metabolismo , Papaína , Linfocitos , Pulmón , Inmunidad Adaptativa , Inflamación , Citocinas/metabolismo , Interleucina-33RESUMEN
Pulmonary fibrosis is a progressive and debilitating lung disease characterized by the excessive accumulation of extracellular matrix (ECM) components within the lung parenchyma. However, the underlying mechanism remains largely elusive, and the treatment options available for pulmonary fibrosis are limited. Interleukin 5 receptor, alpha (IL5RA) is a well-established regulator of eosinophil activation, involved in eosinophil-mediated anti-parasitic activities and allergic reactions. Recent studies have indicated additional roles of IL5RA in lung epithelium and fibroblasts. Nevertheless, its involvement in pulmonary fibrosis remains unclear. In present study, we employed single-cell analyses alongside molecular and cellular assays to unveil the expression of IL5RA in lung epithelial cells. Moreover, using both in vitro and in vivo models, we demonstrated a notable upregulation of epithelial IL5RA during the progression of pulmonary fibrosis. This upregulated IL5RA expression subsequently promotes epithelial-mesenchymal transition (EMT), leading to the generation of mesenchymal phenotype with augmented capability for ECM production. Importantly, our findings uncovered that the pro-fibrotic function of IL5RA is mediated by Jak2/STAT3 signaling cascades. Inhibiting IL5RA has the potential to deactivate Jak2/STAT3 and suppress the downstream EMT process and ECM production, thereby offering a promising therapeutic strategy for pulmonary fibrosis.
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Fibrosis Pulmonar , Humanos , Transición Epitelial-Mesenquimal/fisiología , Fibrosis , Subunidad alfa del Receptor de Interleucina-5/metabolismo , Pulmón/metabolismo , Fibrosis Pulmonar/metabolismo , Receptores de Interleucina-5/metabolismo , Factor de Transcripción STAT3/metabolismoRESUMEN
INTRODUCTION: Near-fatal asthma (NFA) is a severe condition that can lead to respiratory arrest or high carbon dioxide levels, often requiring mechanical ventilation. Biologics have revolutionized the management of severe asthma, significantly improving symptom severity, reducing the number of exacerbations and hospitalizations, and decreasing the need for oral corticosteroids. However, their effectiveness in acute settings, particularly for ICU patients experiencing severe respiratory failure, is not well-studied. More research is needed to determine if biologics can improve recovery during severe asthma exacerbations. CASE STUDY: We report a case of NFA in a patient with severe allergic eosinophilic asthma, who experienced global respiratory failure necessitating hospitalization, intubation, and veno-venous extracorporeal membrane oxygenation (VV-ECMO). Given the severity of the clinical condition, compassionate administration of Benralizumab, which targets the IL-5 receptor, was attempted. RESULTS: Five days from anti-IL5 receptor treatment start, the patient was extubated and the ECMO stopped. After the stepdown to the respiratory intensive care unit (RICU), the patient was weaned from oxygen therapy and subsequently discharged from hospital. CONCLUSION: Benralizumab demonstrated rapid effectiveness in improving respiratory failure leading to successful weaning from VV-ECMO and subsequent extubation.
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INTRODUCTION: Mepolizumab, a humanized anti IL-5 monoclonal antibody, has been used off-label for chronic eosinophilic pneumonia (CEP), inducing disease remission and saving systemic corticosteroids. CASE STUDY: We present a case of CEP, requiring long-term corticosteroids therapy due to relapse upon withdrawal. Mepolizumab was started and maintained for 2 years and 6 months. RESULTS: Corticosteroids could be withdrawn and mepolizumab dose interval was spared up to 10 wk with no disease relapse. CONCLUSION: Mepolizumab is shown to be useful for chronic eosinophilic pneumonia, allowing corticosteroid withdrawal. Dose interval may be individualized under close monitoring, for a more efficient treatment, reducing medical costs while improving patients' quality of life.
Asunto(s)
Antiasmáticos , Asma , Eosinofilia Pulmonar , Humanos , Eosinofilia Pulmonar/tratamiento farmacológico , Asma/tratamiento farmacológico , Calidad de Vida , Enfermedad Crónica , Corticoesteroides/uso terapéutico , Recurrencia , Antiasmáticos/uso terapéuticoRESUMEN
OBJECTIVE: The aim of this retrospective multicentre study is to describe the clinical characteristics of patients diagnosed with severe eosinophilic asthma receiving anti-IL-5/anti-IL-5Rα therapies and to compare their effectiveness. METHODS: We collected and analysed results separately for anti-IL-5 and anti-IL-5Rα therapies from January 2016 until December 2021 in multidisciplinary severe asthma units. We collected demographic and clinical data, treatment with previous anti-IgE and/or anti-IL-5 agents, and comorbidities. We compared the number of exacerbations and admissions to the hospital, daily oral corticosteroid intake, pulmonary function tests, and Asthma Control Test scores before and after 12 months of therapy. 261 patients were included: 176 patients in the anti-IL-5 group and 85 in the anti-IL-5Rα group. RESULTS: Both groups led to statistically significant reductions in asthma exacerbations, hospital admissions, and visits to the Emergency Room. Although both groups showed a significant reduction in blood eosinophiliccount, we found a difference, although not significant, in the magnitude of reduction as benralizumab was able to decrease eosinophil counts to zero. Patients in the anti-IL-5 group achieved higher ACT scores after treatment, although this improvement was seen in both treatment groups. CONCLUSION: The anti-IL-5 and anti-IL-5Rα biologics have shown similar effectiveness despite having different mechanisms of action. The anti-IL-5 group appeared to be better than benralizumab at improving ACT scores and FEV1/FVC and at reducing the number of inhalers. Although these differences were not statistically significant, it is not clear whether they may have clinical relevance and they might highlight the need for further head-to-head studies comparing these treatments.