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Foxp3+ regulatory T (Treg) cells expressing the interleukin (IL)-33 receptor ST2 mediate tissue repair in response to IL-33. Whether Treg cells also respond to the alarmin IL-33 to regulate specific aspects of the immune response is not known. Here we describe an unexpected function of ST2+ Treg cells in suppressing the innate immune response in the lung to environmental allergens without altering the adaptive immune response. Following allergen exposure, ST2+ Treg cells were activated by IL-33 to suppress IL-17-producing γδ T cells. ST2 signaling in Treg cells induced Ebi3, a component of the heterodimeric cytokine IL-35 that was required for Treg cell-mediated suppression of γδ T cells. This response resulted in fewer eosinophil-attracting chemokines and reduced eosinophil recruitment into the lung, which was beneficial to the host in reducing allergen-induced inflammation. Thus, we define a fundamental role for ST2+ Treg cells in the lung as a negative regulator of the early innate γδ T cell response to mucosal injury.
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Inmunomodulación , Interleucina-33/metabolismo , Linfocitos Intraepiteliales/inmunología , Linfocitos Intraepiteliales/metabolismo , Pulmón/inmunología , Pulmón/metabolismo , Linfocitos T Reguladores/inmunología , Linfocitos T Reguladores/metabolismo , Alérgenos/inmunología , Animales , Biomarcadores , Inmunofenotipificación , Proteína 1 Similar al Receptor de Interleucina-1/metabolismo , Leucocitos/inmunología , Leucocitos/metabolismo , RatonesRESUMEN
BACKGROUND: Asthma is often accompanied by type 2 immunity rich in IL-4, IL-5 and IL-13 cytokines produced by TH2 lymphocytes or type 2 innate lymphoid cells (ILC2s). Interleukin-2 family cytokines play a key role in the differentiation, homeostasis and effector function of innate and adaptive lymphocytes. OBJECTIVE: IL-9 and IL-21 boost the activation and proliferation of TH2 and ILC2s, but the relative importance and potential synergism between these γc cytokines is currently unknown. METHODS: Using newly generated antibodies, we inhibited IL-9 and IL-21 alone or in combination, in various murine models of asthma. In a translational approach using segmental allergen challenge, we recently described elevated IL-9 levels in human allergic asthmatics in comparison to non-asthmatic controls. Here, we also measured IL-21 in both groups. RESULTS: IL-9 played a central role in controlling innate IL-33 induced lung inflammation by promoting proliferation and activation of ILC2s, in an IL-21 independent manner. Conversely, chronic house dust mite induced airway inflammation, mainly driven by adaptive immunity, was solely dependent on IL-21, that controlled TH2 activation, eosinophilia, total serum IgE and formation of tertiary lymphoid structures. In a model of innate on adaptive immunity driven by papain allergen, a clear synergy was found between both pathways, since combined anti-IL-9 or anti-IL-21 blockade was superior in reducing key asthma features. In human bronchoalveolar lavage (BAL) samples we measured elevated IL-21 protein within the allergic asthmatic group, compared with the allergic control group. We also found increased IL21R transcripts and predicted IL-21 ligand activity in various disease-associated cell subsets. CONCLUSION: IL-9 and IL-21 play important and non-redundant roles in allergic asthma by boosting ILC2s and TH2 cells, revealing a dual IL-9 and IL-21 targeting strategy as a new and testable approach.
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BACKGROUND: Most genetic studies of asthma and allergy have focused on common variation in individuals primarily of European ancestry. Studying the role of rare variation in quantitative phenotypes and in asthma phenotypes in populations of diverse ancestries can provide additional, important insights into the development of these traits. OBJECTIVE: We sought to examine the contribution of rare variants to different asthma- or allergy-associated quantitative traits in children with diverse ancestries and explore their role in asthma phenotypes. METHODS: We examined whole-genome sequencing data from children participants in longitudinal studies of asthma (n = 1035; parent-identified as 67% Black and 25% Hispanic) to identify rare variants (minor allele frequency < 0.01). We assigned variants to genes and tested for associations using an omnibus variant-set test between each of 24,902 genes and 8 asthma-associated quantitative traits. On combining our results with external data on predicted gene expression in humans and mouse knockout studies, we identified 3 candidate genes. A burden of rare variants in each gene and in a combined 3-gene score was tested for its associations with clinical phenotypes of asthma. Finally, published single-cell gene expression data in lower airway mucosal cells after allergen challenge were used to assess transcriptional responses to allergen. RESULTS: Rare variants in USF1 were significantly associated with blood neutrophil count (P = 2.18 × 10-7); rare variants in TNFRSF21 with total IgE (P = 6.47 × 10-6) and PIK3R6 with eosinophil count (P = 4.10 × 10-5) reached suggestive significance. These 3 findings were supported by independent data from human and mouse studies. A burden of rare variants in TNFRSF21 and in a 3-gene score was associated with allergy-related phenotypes in cohorts of children with mild and severe asthma. Furthermore, TNFRSF21 was significantly upregulated in bronchial basal epithelial cells from adults with allergic asthma but not in adults with allergies (but not asthma) after allergen challenge. CONCLUSIONS: We report novel associations between rare variants in genes and allergic and inflammatory phenotypes in children with diverse ancestries, highlighting TNFRSF21 as contributing to the development of allergic asthma.
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Asma , Hipersensibilidad , Adulto , Niño , Humanos , Animales , Ratones , Asma/genética , Hipersensibilidad/genética , Estudios de Asociación Genética , Fenotipo , Alérgenos , Polimorfismo de Nucleótido Simple , Estudio de Asociación del Genoma Completo , Receptores del Factor de Necrosis TumoralRESUMEN
The mammalian airways and lungs are exposed to a myriad of inhaled particulate matter, allergens, and pathogens. The immune system plays an essential role in protecting the host from respiratory pathogens, but a dysregulated immune response during respiratory infection can impair pathogen clearance and lead to immunopathology. Furthermore, inappropriate immunity to inhaled antigens can lead to pulmonary diseases. A complex network of epithelial, neural, stromal, and immune cells has evolved to sense and respond to inhaled antigens, including the decision to promote tolerance versus a rapid, robust, and targeted immune response. Although there has been great progress in understanding the mechanisms governing immunity to respiratory pathogens and aeroantigens, we are only beginning to develop an integrated understanding of the cellular networks governing tissue immunity within the lungs and how it changes after inflammation and over the human life course. An integrated model of airway and lung immunity will be necessary to improve mucosal vaccine design as well as prevent and treat acute and chronic inflammatory pulmonary diseases. Given the importance of immunology in pulmonary research, the American Thoracic Society convened a working group to highlight central areas of investigation to advance the science of lung immunology and improve human health.
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Enfermedades Pulmonares , Infecciones del Sistema Respiratorio , Animales , Humanos , Pulmón , Mamíferos , Material Particulado , TóraxRESUMEN
Background The long-term effects of SARS-CoV-2 infection on pulmonary structure and function remain incompletely characterized. Purpose To test whether SARS-CoV-2 infection leads to small airways disease in patients with persistent symptoms. Materials and Methods In this single-center study at a university teaching hospital, adults with confirmed COVID-19 who remained symptomatic more than 30 days following diagnosis were prospectively enrolled from June to December 2020 and compared with healthy participants (controls) prospectively enrolled from March to August 2018. Participants with post-acute sequelae of COVID-19 (PASC) were classified as ambulatory, hospitalized, or having required the intensive care unit (ICU) based on the highest level of care received during acute infection. Symptoms, pulmonary function tests, and chest CT images were collected. Quantitative CT analysis was performed using supervised machine learning to measure regional ground-glass opacity (GGO) and using inspiratory and expiratory image-matching to measure regional air trapping. Univariable analyses and multivariable linear regression were used to compare groups. Results Overall, 100 participants with PASC (median age, 48 years; 66 women) were evaluated and compared with 106 matched healthy controls; 67% (67 of 100) of the participants with PASC were classified as ambulatory, 17% (17 of 100) were hospitalized, and 16% (16 of 100) required the ICU. In the hospitalized and ICU groups, the mean percentage of total lung classified as GGO was 13.2% and 28.7%, respectively, and was higher than that in the ambulatory group (3.7%, P < .001 for both comparisons). The mean percentage of total lung affected by air trapping was 25.4%, 34.6%, and 27.3% in the ambulatory, hospitalized, and ICU groups, respectively, and 7.2% in healthy controls (P < .001). Air trapping correlated with the residual volume-to-total lung capacity ratio (ρ = 0.6, P < .001). Conclusion In survivors of COVID-19, small airways disease occurred independently of initial infection severity. The long-term consequences are unknown. © RSNA, 2022 Online supplemental material is available for this article. See also the editorial by Elicker in this issue.
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COVID-19/complicaciones , Enfermedades Pulmonares , COVID-19/diagnóstico por imagen , Femenino , Humanos , Enfermedades Pulmonares/diagnóstico por imagen , Enfermedades Pulmonares/virología , Masculino , Persona de Mediana Edad , Tomografía Computarizada por Rayos X/métodos , Síndrome Post Agudo de COVID-19RESUMEN
Rationale: Standard physiologic assessments of extubation readiness in patients with acute hypoxemic respiratory failure (AHRF) may not reflect lung injury resolution and could adversely affect clinical decision-making and patient outcomes. Objectives: We hypothesized that elevations in inflammatory plasma biomarkers sST2 (soluble suppression of tumorigenicity-2) and IL-6 indicate ongoing lung injury in AHRF and better inform patient outcomes compared with standard clinical assessments. Methods: We measured daily plasma biomarkers and physiologic variables in 200 patients with AHRF for up to 9 days after intubation. We tested the associations of baseline values with the primary outcome of unassisted breathing at Day 29. We analyzed the ability of serial biomarker measurements to inform successful ventilator liberation. Measurements and Main Results: Baseline sST2 concentrations were higher in patients dead or mechanically ventilated versus breathing unassisted at Day 29 (491.7 ng/ml [interquartile range (IQR), 294.5-670.1 ng/ml] vs. 314.4 ng/ml [IQR, 127.5-550.1 ng/ml]; P = 0.0003). Higher sST2 concentrations over time were associated with a decreased probability of ventilator liberation (hazard ratio, 0.80 per log-unit increase; 95% confidence interval [CI], 0.75-0.83; P = 0.03). Patients with higher sST2 concentrations on the day of liberation were more likely to fail liberation compared with patients who remained successfully liberated (320.9 ng/ml [IQR, 181.1- 495.6 ng/ml] vs. 161.6 ng/ml [IQR, 95.8-292.5 ng/ml]; P = 0.002). Elevated sST2 concentrations on the day of liberation decreased the odds of successful liberation when adjusted for standard physiologic parameters (odds ratio, 0.325; 95% CI, 0.119-0.885; P = 0.03). IL-6 concentrations did not associate with outcomes. Conclusions: Using sST2 concentrations to guide ventilator management may more accurately reflect underlying lung injury and outperform traditional measures of readiness for ventilator liberation.
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Proteína 1 Similar al Receptor de Interleucina-1/sangre , Insuficiencia Respiratoria/sangre , Insuficiencia Respiratoria/terapia , Desconexión del Ventilador , Adulto , Anciano , Extubación Traqueal , Biomarcadores/sangre , Femenino , Mortalidad Hospitalaria , Humanos , Interleucina-6/sangre , Masculino , Persona de Mediana Edad , Oportunidad Relativa , Selección de Paciente , Insuficiencia Respiratoria/mortalidad , Factores de TiempoRESUMEN
Smoking and human immunodeficiency virus 1 (HIV-1) infection are risk factors for chronic obstructive pulmonary disease (COPD), which is among the most common comorbid conditions in people living with HIV-1. HIV-1 infection leads to persistent expansion of CD8+ T cells, and CD8+ T cell-mediated inflammation has been implicated in COPD pathogenesis. In this study, we investigated the effects of HIV-1 infection and smoking on T-cell dynamics in patients at risk of COPD. BAL fluid, endobronchial brushings, and blood from HIV-1 infected and uninfected nonsmokers and smokers were analyzed by flow cytometry, and lungs were imaged by computed tomography. Chemokines were measured in BAL fluid, and CD8+ T-cell chemotaxis in the presence of cigarette smoke extract was assessed in vitro. HIV-1 infection increased CD8+ T cells in the BAL fluid, but this increase was abrogated by smoking. Smokers had reduced BAL fluid concentrations of the T cell-recruiting chemokines CXCL10 and CCL5, and cigarette smoke extract inhibited CXCL10 and CCL5 production by macrophages and CD8+ T-cell transmigration in vitro. In contrast to the T cells in BAL fluid, CD8+ T cells in endobronchial brushings were increased in HIV-1-infected smokers, which was driven by an accumulation of effector memory T cells in the airway mucosa and an increase in tissue-resident memory T cells. Mucosal CD8+ T-cell numbers inversely correlated with lung aeration, suggesting an association with inflammation and remodeling. HIV-1 infection and smoking lead to retention of CD8+ T cells within the airway mucosa.
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Linfocitos T CD8-positivos/patología , Infecciones por VIH/patología , Enfermedad Pulmonar Obstructiva Crónica/patología , Mucosa Respiratoria/patología , Fumar/efectos adversos , Adulto , Líquido del Lavado Bronquioalveolar , Linfocitos T CD8-positivos/virología , Quimiocina CCL5/metabolismo , Quimiocina CXCL10/metabolismo , Quimiotaxis , Femenino , VIH-1/patogenicidad , Humanos , Masculino , Persona de Mediana Edad , Membrana Mucosa/patología , Membrana Mucosa/virología , Enfermedad Pulmonar Obstructiva Crónica/etiología , Receptores CCR5/metabolismo , Receptores CXCR3/metabolismo , Mucosa Respiratoria/efectos de los fármacos , Mucosa Respiratoria/virología , Factores de Riesgo , Tomografía Computarizada por Rayos X , Carga ViralRESUMEN
Cellular plasticity contributes to the regenerative capacity of plants, invertebrates, teleost fishes and amphibians. In vertebrates, differentiated cells are known to revert into replicating progenitors, but these cells do not persist as stable stem cells. Here we present evidence that differentiated airway epithelial cells can revert into stable and functional stem cells in vivo. After the ablation of airway stem cells, we observed a surprising increase in the proliferation of committed secretory cells. Subsequent lineage tracing demonstrated that the luminal secretory cells had dedifferentiated into basal stem cells. Dedifferentiated cells were morphologically indistinguishable from stem cells and they functioned as well as their endogenous counterparts in repairing epithelial injury. Single secretory cells clonally dedifferentiated into multipotent stem cells when they were cultured ex vivo without basal stem cells. By contrast, direct contact with a single basal stem cell was sufficient to prevent secretory cell dedifferentiation. In analogy to classical descriptions of amphibian nuclear reprogramming, the propensity of committed cells to dedifferentiate is inversely correlated to their state of maturity. This capacity of committed cells to dedifferentiate into stem cells may have a more general role in the regeneration of many tissues and in multiple disease states, notably cancer.
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Desdiferenciación Celular , Células Epiteliales/citología , Células Madre/citología , Animales , Antineoplásicos Hormonales/farmacología , Proliferación Celular/efectos de los fármacos , Supervivencia Celular , Células Cultivadas , Doxiciclina/farmacología , Células Epiteliales/efectos de los fármacos , Femenino , Masculino , Ratones Transgénicos , Células Madre/efectos de los fármacos , Tamoxifeno/farmacologíaRESUMEN
BACKGROUND AND OBJECTIVE: In vivo evaluation of the microstructural differences between asthmatic and non-asthmatic airways and their functional consequences is relevant to understanding and, potentially, treating asthma. In this study, we use endobronchial optical coherence tomography to investigate how allergic airways with asthma differ from allergic non-asthmatic airways in baseline microstructure and in response to allergen challenge. METHODS: A total of 45 subjects completed the study, including 20 allergic, mildly asthmatic individuals, 22 non-asthmatic allergic controls and 3 healthy controls. A 3-cm airway segment in the right middle and right upper lobe were imaged in each subject immediately before and 24 h following segmental allergen challenge to the right middle lobe. Relationships between optical airway measurements (epithelial and mucosal thicknesses, mucosal buckling and mucus) and airway obstruction (FEV1 /FVC (forced expiratory volume in 1 s/forced vital capacity) and FEV1 % (FEV1 as a percentage of predictive value)) were investigated. RESULTS: Significant increases at baseline and in response to allergen were observed for all four of our imaging metrics in the asthmatic airways compared to the non-asthmatic airways. Epithelial thickness and mucosal buckling exhibited a significant relationship to FEV1 /FVC in the asthmatic group. CONCLUSION: Simultaneous assessments of airway microstructure, buckling and mucus revealed both structural and functional differences between the mildly asthmatic and control groups, with airway buckling seeming to be the most relevant factor. The results of this study demonstrate that a comprehensive, microstructural approach to assessing the airways may be important in future asthma studies as well as in the monitoring and treatment of asthma.
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Remodelación de las Vías Aéreas (Respiratorias) , Alérgenos/inmunología , Asma , Pulmón , Hipersensibilidad Respiratoria , Tomografía de Coherencia Óptica/métodos , Adulto , Asma/diagnóstico , Asma/inmunología , Asma/fisiopatología , Pruebas de Provocación Bronquial/métodos , Broncoscopía/métodos , Femenino , Humanos , Pulmón/diagnóstico por imagen , Pulmón/fisiopatología , Masculino , Pruebas de Función Respiratoria/métodos , Hipersensibilidad Respiratoria/diagnóstico , Hipersensibilidad Respiratoria/inmunología , Hipersensibilidad Respiratoria/fisiopatologíaRESUMEN
The airway epithelial cell (AEC) response to allergens helps initiate and propagate allergic inflammation in asthma. CARMA3 is a scaffold protein that mediates G protein-coupled receptor-induced NF-κB activation in airway epithelium. In this study, we demonstrate that mice with CARMA3-deficient AECs have reduced airway inflammation, as well as reduced type 2 cytokine levels in response to Alternaria alternata. These mice also have reduced production of IL-33 and IL-25, and reduced numbers of innate lymphoid cells in the lung. We also show that CARMA3-deficient human AECs have decreased production of proasthmatic mediators in response to A. alternata. Finally, we show that CARMA3 interacts with inositol 1,4,5-trisphosphate receptors in AECs, and that inhibition of CARMA3 signaling reduces A. alternata-induced intracellular calcium release. In conclusion, we show that CARMA3 signaling in AECs helps mediate A. alternata-induced allergic airway inflammation, and that CARMA3 is an important signaling molecule for type 2 immune responses in the lung.
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Alérgenos/inmunología , Alternaria/fisiología , Alternariosis/inmunología , Asma/inmunología , Proteínas Adaptadoras de Señalización CARD/metabolismo , Neumonía/inmunología , Alérgenos/metabolismo , Alternariosis/metabolismo , Alternariosis/microbiología , Animales , Asma/metabolismo , Asma/microbiología , Células Cultivadas , Modelos Animales de Enfermedad , Humanos , Ratones , Neumonía/metabolismo , Neumonía/microbiologíaRESUMEN
Innate immune responses to allergens by airway epithelial cells (AECs) help initiate and propagate the adaptive immune response associated with allergic airway inflammation in asthma. Activation of the transcription factor NF-κB in AECs by allergens or secondary mediators via G protein-coupled receptors (GPCRs) is an important component of this multifaceted inflammatory cascade. Members of the caspase recruitment domain family of proteins display tissue-specific expression and help mediate NF-κB activity in response to numerous stimuli. We have previously shown that caspase recruitment domain-containing membrane-associated guanylate kinase protein (CARMA)3 is specifically expressed in AECs and mediates NF-κB activation in these cells in response to stimulation with the GPCR agonist lysophosphatidic acid. In this study, we demonstrate that reduced levels of CARMA3 in normal human bronchial epithelial cells decreases the production of proasthmatic mediators in response to a panel of asthma-relevant GPCR ligands such as lysophosphatidic acid, adenosine triphosphate, and allergens that activate GPCRs such as Alternaria alternata and house dust mite. We then show that genetically modified mice with CARMA3-deficient AECs have reduced airway eosinophilia and proinflammatory cytokine production in a murine model of allergic airway inflammation. Additionally, we demonstrate that these mice have impaired dendritic cell maturation in the lung and that dendritic cells from mice with CARMA3-deficient AECs have impaired Ag processing. In conclusion, we show that AEC CARMA3 helps mediate allergic airway inflammation, and that CARMA3 is a critical signaling molecule bridging the innate and adaptive immune responses in the lung.
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Asma/inmunología , Proteínas Adaptadoras de Señalización CARD/inmunología , Células Dendríticas/inmunología , Células Epiteliales/inmunología , Pulmón/inmunología , Inmunidad Adaptativa , Adenosina Trifosfato/farmacología , Alérgenos/inmunología , Alternaria/inmunología , Animales , Asma/inducido químicamente , Asma/genética , Asma/patología , Proteínas Adaptadoras de Señalización CARD/deficiencia , Proteínas Adaptadoras de Señalización CARD/genética , Células Cultivadas , Citocinas/biosíntesis , Citocinas/inmunología , Células Dendríticas/efectos de los fármacos , Células Dendríticas/patología , Células Epiteliales/efectos de los fármacos , Células Epiteliales/patología , Femenino , Regulación de la Expresión Génica , Inmunidad Innata , Pulmón/efectos de los fármacos , Pulmón/patología , Lisofosfolípidos/farmacología , Masculino , Ratones , Ratones Endogámicos C57BL , Ratones Transgénicos , FN-kappa B/genética , FN-kappa B/inmunología , Ovalbúmina/inmunología , Pyroglyphidae/inmunología , Transducción de SeñalRESUMEN
Mass cytometry (CyTOF), a mass spectrometry-based single cell phenotyping technology, allows utilization of over 35 antibodies in a single sample and is a promising tool for translational human immunology studies. Although several analysis tools are available to interpret the complex data sets generated, a robust method for standardization and quality control within and across studies is needed. Here we report an efficient and easily adaptable method to monitor quality of individual samples in human immunology studies and to facilitate reproducible data analysis. Samples to be assessed are spiked with a defined amount of reference peripheral blood mononuclear cells from a healthy donor, derived from a single large blood draw. The presence of known standardized numbers and phenotypic profiles of these reference cells greatly facilitates sample analysis by allowing for: 1) quality control for consistent staining of each antibody in the panel, 2) identification of potential batch effects, and 3) implementation of a robust gating strategy. We demonstrate the utility of this method using peripheral blood and bronchoalveolar lavage samples from HIV+ patients by characterizing their CD8+ T-cell phenotypes and cytokine expression, respectively. Our results indicate that this method allows quality control of experimental conditions and results in highly reproducible population frequencies through a robust gating strategy. © 2016 International Society for Advancement of Cytometry.
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Citometría de Flujo/métodos , Espectrometría de Masas/métodos , Anticuerpos/metabolismo , Lavado Broncoalveolar/métodos , Linfocitos T CD8-positivos/citología , Linfocitos T CD8-positivos/metabolismo , Citocinas/metabolismo , Infecciones por VIH/metabolismo , Humanos , Inmunofenotipificación/métodos , Leucocitos Mononucleares/citología , Leucocitos Mononucleares/metabolismo , Control de Calidad , Estándares de Referencia , Reproducibilidad de los ResultadosRESUMEN
Influenza is a major cause of morbidity and mortality in the United States. Studies have shown that excessive T cell activity can mediate pneumonitis in the setting of influenza infection, and data from the 2009 H1N1 pandemic indicate that critical illness and respiratory failure postinfection were associated with greater infiltration of the lungs with CD8+ T cells. T cell Ig and mucin domain 3 (Tim3) is a negative regulator of Th1/Tc1-type immune responses. Activation of Tim3 on effector T cells has been shown to downregulate proliferation, cell-mediated cytotoxicity, and IFN-γ production, as well as induce apoptosis. In this article, we demonstrate that deletion of the terminal cytoplasmic domain of the Tim3 gene potentiates its ability to downregulate Tc1 inflammation, and that this enhanced Tim3 activity is associated with decreased phosphorylation of the TCR-CD3ζ-chain. We then show that mice with this Tim3 mutation infected with influenza are protected from morbidity and mortality without impairment in viral clearance or functional heterotypic immunity. This protection is associated with decreased CD8+ T cell proliferation and decreased production of inflammatory cytokines, including IFN-γ. Furthermore, the Tim3 mutation was protective against mortality in a CD8+ T cell-specific model of pneumonitis. These data suggest that Tim3 could be targeted to prevent immunopathology during influenza infection and demonstrate a potentially novel signaling mechanism used by Tim3 to downregulate the Tc1 response.
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Infecciones por Orthomyxoviridae/inmunología , Receptores Virales/metabolismo , Regulación hacia Arriba/inmunología , Animales , Complejo CD3/metabolismo , Linfocitos T CD8-positivos/inmunología , Linfocitos T CD8-positivos/metabolismo , Linfocitos T CD8-positivos/patología , Citotoxicidad Inmunológica/genética , Modelos Animales de Enfermedad , Regulación hacia Abajo/genética , Regulación hacia Abajo/inmunología , Receptor 2 Celular del Virus de la Hepatitis A , Ratones , Ratones Endogámicos C57BL , Ratones Transgénicos , Infecciones por Orthomyxoviridae/genética , Infecciones por Orthomyxoviridae/mortalidad , Fosforilación/genética , Fosforilación/inmunología , Receptores Virales/genética , Receptores Virales/fisiología , Eliminación de Secuencia/genética , Eliminación de Secuencia/inmunología , Transducción de Señal/genética , Transducción de Señal/inmunología , Análisis de Supervivencia , Regulación hacia Arriba/genéticaRESUMEN
BACKGROUND: Induction of endogenous regulatory T (Treg) cells represents an exciting new potential modality for treating allergic diseases, such as asthma. Treg cells have been implicated in the regulation of asthma, but the anatomic location in which they exert their regulatory function and the mechanisms controlling the migration necessary for their suppressive function in asthma are not known. Understanding these aspects of Treg cell biology will be important for harnessing their power in the clinic. OBJECTIVE: We sought to determine the anatomic location at which Treg cells exert their regulatory function in the sensitization and effector phases of allergic asthma and to determine the chemokine receptors that control the migration of Treg cells to these sites in vivo in both mice and human subjects. METHODS: The clinical efficacy and anatomic location of adoptively transferred chemokine receptor-deficient CD4(+)CD25(+) forkhead box protein 3-positive Treg cells was determined in the sensitization and effector phases of allergic airway inflammation in mice. The chemokine receptor expression profile was determined on Treg cells recruited into the human airway after bronchoscopic segmental allergen challenge of asthmatic patients. RESULTS: We show that CCR7, but not CCR4, is required on Treg cells to suppress allergic airway inflammation during the sensitization phase. In contrast, CCR4, but not CCR7, is required on Treg cells to suppress allergic airway inflammation during the effector phase. Consistent with our murine studies, human subjects with allergic asthma had an increase in CCR4-expressing functional Treg cells in the lungs after segmental allergen challenge. CONCLUSION: The location of Treg cell function differs during allergic sensitization and allergen-induced recall responses in the lung, and this differential localization is critically dependent on differential chemokine function.
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Asma/inmunología , Asma/metabolismo , Quimiocinas/metabolismo , Linfocitos T Reguladores/inmunología , Linfocitos T Reguladores/metabolismo , Alérgenos/inmunología , Animales , Asma/genética , Líquido del Lavado Bronquioalveolar/citología , Líquido del Lavado Bronquioalveolar/inmunología , Movimiento Celular/inmunología , Modelos Animales de Enfermedad , Expresión Génica , Técnicas de Inactivación de Genes , Humanos , Inmunización , Inflamación/genética , Inflamación/inmunología , Inflamación/metabolismo , Pulmón/inmunología , Pulmón/metabolismo , Pulmón/patología , Ratones , Receptores CCR4/deficiencia , Receptores CCR4/genética , Receptores CCR7/deficiencia , Receptores CCR7/genéticaRESUMEN
Background: Many of those infected with COVID-19 experience long-term disability due to persistent symptoms known as Long-COVID, which include ongoing respiratory issues, loss of taste and smell, and impaired daily functioning. Research Question: This study aims to better understand the chronology of long-COVID symptoms. Study Design and Methods: We prospectively enrolled 403 adults from the University of Iowa long-COVID clinic (June 2020 to February 2022). Participants provided symptom data during acute illness, symptom progression, and other clinical characteristics. Patients in this registry received a survey containing questions including current symptoms and status since long-COVID diagnosis (sliding status scale, PHQ2, GAD2, MMRC). Those >12 months since acute-COVID diagnosis had chart review done to track their symptomology. Results: Of 403 participants contacted, 129 (32%) responded. The mean age (in years) was 50.17 +/-14.28, with 31.8% male and 68.2% female. Severity of acute covid treatment was stratified by treatment in the outpatient (70.5%), inpatient (16.3%), or ICU (13.2%) settings. 51.2% reported subjective improvement (sliding scale scores of 67-100) since long-COVID onset. Ages 18-29 reported significantly higher subjective status scores. Subjective status scores were unaffected by severity. 102 respondents were >12 months from their initial COVID-19 diagnosis and were tracked for longitudinal symptom persistence. All symptoms tracked had variance (mean fraction 0.58, range 0.34-0.75) in the reported symptoms at the time of long-COVID presentation when compared with patient survey report. 48 reported persistent dyspnea, 23 (48%) had resolved it at time of survey. For fatigue, 44 had persistence, 12 (27%) resolved. Interpretation: Overall, 51.2% respondents improved since their long-COVID began. Pulmonary symptoms were more persistent than neuromuscular symptoms (anosmia, dysgeusia, myalgias). Gender, time since acute COVID infection, and its severity didn't affect subjective status or symptoms. This study highlights recall bias that may be prevalent in other long-COVID research reliant on participant memory.
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Adult stem cells play a crucial role in tissue homeostasis and repair through multiple mechanisms. In addition to being able to replace aged or damaged cells, stem cells provide signals that contribute to the maintenance and function of neighboring cells. In the lung, airway basal stem cells also produce cytokines and chemokines in response to inhaled irritants, allergens, and pathogens, which affect specific immune cell populations and shape the nature of the immune response. However, direct cell-to-cell signaling through contact between airway basal stem cells and immune cells has not been demonstrated. Recently, a unique population of intraepithelial airway macrophages (IAMs) has been identified in the murine trachea. Here, we demonstrate that IAMs require Notch signaling from airway basal stem cells for maintenance of their differentiated state and function. Furthermore, we demonstrate that Notch signaling between airway basal stem cells and IAMs is required for antigen-induced allergic inflammation only in the trachea where the basal stem cells are located whereas allergic responses in distal lung tissues are preserved consistent with a local circuit linking stem cells to proximate immune cells. Finally, we demonstrate that IAM-like cells are present in human conducting airways and that these cells display Notch activation, mirroring their murine counterparts. Since diverse lung stem cells have recently been identified and localized to specific anatomic niches along the proximodistal axis of the respiratory tree, we hypothesize that the direct functional coupling of local stem cell-mediated regeneration and immune responses permits a compartmentalized inflammatory response.
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Vacuna BCG/efectos adversos , Pulmón/patología , Mycobacterium bovis/aislamiento & purificación , Tuberculosis/patología , Anciano , Alveolitis Alérgica Extrínseca/diagnóstico , Vacuna BCG/uso terapéutico , Biopsia , Carcinoma de Células Transicionales/complicaciones , Carcinoma de Células Transicionales/tratamiento farmacológico , Diagnóstico Diferencial , Fiebre/etiología , Humanos , Leucopenia/etiología , Pulmón/diagnóstico por imagen , Masculino , Radiografía , Tuberculosis/diagnóstico por imagen , Tuberculosis/etiología , Neoplasias de la Vejiga Urinaria/complicaciones , Neoplasias de la Vejiga Urinaria/tratamiento farmacológicoRESUMEN
Lung transplantation remains the only effective therapy for patients with end-stage pulmonary diseases. Unfortunately, acute rejection of the lung remains a frequent complication and is an important cause of morbidity and mortality. The induction of transplant tolerance is thought to be dependent, in part, on the balance between allograft effector mechanisms mediated by effector T lymphocytes (Teff), and regulatory mechanisms mediated by FOXP3(+) regulatory T cells (Treg). In this study, we explored an approach to tip the balance in favor of regulatory mechanisms by modulating chemokine activity. We demonstrate in an adoptive transfer model of lung rejection that CXCR3-deficient CD8(+) Teff have impaired migration into the lungs compared with wild-type Teff, which results in a dramatic reduction in fatal pulmonary inflammation. The lungs of surviving mice contained tolerized CXCR3-deficient Teff, as well as a large increase in Treg. We confirmed that Treg were needed for tolerance and that their ability to induce tolerance was dependent on their numbers in the lung relative to the numbers of Teff. These data suggest that transplantation tolerance can be achieved by reducing the recruitment of some, but not necessarily all, CD8(+) Teff into the target organ and suggest a novel approach to achieve transplant tolerance.
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Linfocitos T CD8-positivos/inmunología , Quimiotaxis de Leucocito/inmunología , Rechazo de Injerto/prevención & control , Trasplante de Pulmón/inmunología , Receptores CXCR3/inmunología , Tolerancia al Trasplante/inmunología , Animales , Rechazo de Injerto/inmunología , Inflamación/prevención & control , Trasplante de Pulmón/efectos adversos , Ratones , Linfocitos T Reguladores/inmunologíaRESUMEN
BACKGROUND: Chronic electronic-cigarette (EC) use is reported to decrease vascular endothelial function. However, the mechanism(s) mediating this reduction remain unclear. In this study, we examined endothelium- and NO-dependent dilation, and the role of oxidative stress in attenuating these responses, in healthy young EC users (n=20, 10 males/10 females) compared with healthy controls (n=20, 10 males/10 females). We hypothesized that EC would have reduced endothelium- and NO-dependent dilation and administration of the superoxide scavenger tempol would increase these responses in EC. We further hypothesized that female EC would have the greatest reductions in endothelium- and NO-dependent dilation. METHODS: We assessed microvascular endothelium-dependent vasodilator function in vivo by measurement of cutaneous vascular conductance (%CVCmax) responses to a standardized local heating protocol in control and 10 µM tempol-treated sites. After full expression of the local heating response, 15 mM NG-nitro-L-arginine methyl ester (NO synthase inhibition) was perfused. RESULTS: EC had significantly reduced endothelium- (73±15 versus 87±9%CVCmax; P<0.001) and NO-dependent (48±17% versus 62±15%; P=0.011) dilation. Tempol perfusion increased endothelium-dependent (84±12%CVCmax P=0.01) and NO-dependent (63±14% P=0.005) dilation in EC but had no effect in healthy control. Within female sex, EC had lower endothelium-dependent (71±13 versus 89±7%CVCmax; P=0.002) and NO-dependent (50±6 versus 69±11%; P=0.005) dilation compared with healthy control, and tempol augmented endothelium-dependent (83±13%CVCmax; P=0.002) and NO-dependent (62±13%; P=0.015) dilation. There were no group or treatment differences within male sex. CONCLUSION: Healthy young adult EC users have reduced microvascular endothelium-dependent and NO-dependent dilation, driven by greater reductions in female EC users, and mediated in part by superoxide.