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The role of innate immune cells in allergen immunotherapy that confers immune tolerance to the sensitizing allergen is unclear. Here, we report a role of interleukin-10-producing type 2 innate lymphoid cells (IL-10+ ILC2s) in modulating grass-pollen allergy. We demonstrate that KLRG1+ but not KLRG1- ILC2 produced IL-10 upon activation with IL-33 and retinoic acid. These cells attenuated Th responses and maintained epithelial cell integrity. IL-10+ KLRG1+ ILC2s were lower in patients with grass-pollen allergy when compared to healthy subjects. In a prospective, double-blind, placebo-controlled trial, we demonstrated that the competence of ILC2 to produce IL-10 was restored in patients who received grass-pollen sublingual immunotherapy. The underpinning mechanisms were associated with the modification of retinol metabolic pathway, cytokine-cytokine receptor interaction, and JAK-STAT signaling pathways in the ILCs. Altogether, our findings underscore the contribution of IL-10+ ILC2s in the disease-modifying effect by allergen immunotherapy.
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Interleucina-10/metabolismo , Linfocitos/inmunología , Rinitis Alérgica Estacional/inmunología , Inmunoterapia Sublingual/métodos , Adulto , Alérgenos/inmunología , Método Doble Ciego , Femenino , Humanos , Tolerancia Inmunológica , Inmunidad Innata , Quinasas Janus/metabolismo , Lectinas Tipo C/metabolismo , Masculino , Persona de Mediana Edad , Efecto Placebo , Poaceae/inmunología , Polen/inmunología , Receptores Inmunológicos/metabolismo , Rinitis Alérgica Estacional/terapia , Factores de Transcripción STAT/metabolismo , Transducción de Señal , Células Th2/inmunología , Resultado del Tratamiento , Vitamina A/metabolismo , Adulto JovenRESUMEN
Group 2 innate lymphoid cells (ILC2s) secrete type 2 cytokines, which protect against parasites but can also contribute to a variety of inflammatory airway diseases. We report here that interleukin 1ß (IL-1ß) directly activated human ILC2s and that IL-12 induced the conversion of these activated ILC2s into interferon-γ (IFN-γ)-producing ILC1s, which was reversed by IL-4. The plasticity of ILCs was manifested in diseased tissues of patients with severe chronic obstructive pulmonary disease (COPD) or chronic rhinosinusitis with nasal polyps (CRSwNP), which displayed IL-12 or IL-4 signatures and the accumulation of ILC1s or ILC2s, respectively. Eosinophils were a major cellular source of IL-4, which revealed cross-talk between IL-5-producing ILC2s and IL-4-producing eosinophils. We propose that IL-12 and IL-4 govern ILC2 functional identity and that their imbalance results in the perpetuation of type 1 or type 2 inflammation.
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Plasticidad de la Célula , Eosinófilos/inmunología , Inmunidad Innata , Interleucina-12/metabolismo , Interleucina-1beta/metabolismo , Interleucina-4/metabolismo , Linfocitos/inmunología , Pólipos Nasales/inmunología , Neumonía/inmunología , Enfermedad Pulmonar Obstructiva Crónica/inmunología , Rinitis/inmunología , Sinusitis/inmunología , Animales , Diferenciación Celular , Células Cultivadas , Femenino , Humanos , Interferón gamma/metabolismo , Activación de Linfocitos , Ratones , Ratones SCID , Células TH1/inmunología , Balance Th1 - Th2 , Células Th2/inmunologíaRESUMEN
There are ample data to suggest that early-life dysbiosis of both the gut and/or airway microbiome can predispose a child to develop along a trajectory toward asthma. Although individual studies show clear associations between dysbiosis and asthma development, it is less clear what (collection of) bacterial species is mechanistically responsible for the observed effects. This is partly due to issues related to the asthma diagnosis and the broad spectrum of anatomical sites, sample techniques, and analysis protocols that are used in different studies. Moreover, there is limited attention for potential differences in the genetics of individuals that would affect the outcome of the interaction between the environment and that individual. Despite these challenges, the first bacterial components were identified that are able to affect the transcriptional state of human cells, ergo the immune system. Such molecules could in the future be the basis for intervention studies that are now (necessarily) restricted to a limited number of bacterial species. For this transition, it might be prudent to develop an ex vivo human model of a local mucosal immune system to better and safer explore the impact of such molecules. With this approach, we might move beyond association toward understanding of causality.
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Asma , Microbiota , Niño , Humanos , DisbiosisRESUMEN
Innate lymphoid cells (ILCs) are emerging as a family of effectors and regulators of innate immunity and tissue remodeling. Interleukin 22 (IL-22)- and IL-17-producing ILCs, which depend on the transcription factor RORγt, express CD127 (IL-7 receptor α-chain) and the natural killer cell marker CD161. Here we describe another lineage-negative CD127(+)CD161(+) ILC population found in humans that expressed the chemoattractant receptor CRTH2. These cells responded in vitro to IL-2 plus IL-25 and IL-33 by producing IL-13. CRTH2(+) ILCs were present in fetal and adult lung and gut. In fetal gut, these cells expressed IL-13 but not IL-17 or IL-22. There was enrichment for CRTH2(+) ILCs in nasal polyps of chronic rhinosinusitis, a typical type 2 inflammatory disease. Our data identify a unique type of human ILC that provides an innate source of T helper type 2 (T(H)2) cytokines.
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Citocinas/metabolismo , Inmunidad Innata , Linfocitos/metabolismo , Subfamilia B de Receptores Similares a Lectina de Células NK/metabolismo , Receptores Inmunológicos/metabolismo , Receptores de Prostaglandina/metabolismo , Rinitis/inmunología , Sinusitis/inmunología , Adulto , Diferenciación Celular , Linaje de la Célula , Células Cultivadas , Enfermedad Crónica , Citocinas/inmunología , Humanos , Inmunofenotipificación , Interleucina-17/inmunología , Interleucina-17/metabolismo , Interleucina-33 , Interleucinas/inmunología , Interleucinas/metabolismo , Intestinos/patología , Linfocitos/inmunología , Linfocitos/patología , Subfamilia B de Receptores Similares a Lectina de Células NK/inmunología , Pólipos Nasales , Receptores Inmunológicos/inmunología , Receptores de Prostaglandina/inmunología , Rinitis/patología , Rinitis/fisiopatología , Sinusitis/patología , Sinusitis/fisiopatología , Células Th2/inmunología , Células Th2/metabolismoRESUMEN
Type 2 innate lymphoid cells (ILC2s) are part of a large family of ILCs that are important effectors in innate immunity, lymphoid organogenesis, and tissue remodeling. ILC2s mediate parasite expulsion but also contribute to airway inflammation, emphasizing the functional similarity between these cells and Th2 cells. Consistent with this, we report that the transcription factor GATA3 was highly expressed by human ILC2s. CRTH2(+) ILC2s were enriched in nasal polyps of patients with chronic rhinosinusitis, a typical type 2-mediated disease. Nasal polyp epithelial cells expressed TSLP, which enhanced STAT5 activation, GATA3 expression, and type 2 cytokine production in ILC2s. Ectopic expression of GATA3 in Lin(-)CD127(+)CRTH2(-) cells resulted in induction of CRTH2 and the capacity to produce high amounts of type 2 cytokines in response to TSLP plus IL-33. Hence, we identify GATA3, potently regulated by TSLP, as an essential transcription factor for the function of human ILC2s.
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Factor de Transcripción GATA3/inmunología , Inmunidad Innata , Linfocitos/inmunología , Línea Celular , Citocinas/inmunología , Epitelio/inmunología , Regulación de la Expresión Génica , Humanos , Interleucina-13/biosíntesis , Interleucina-13/inmunología , Pólipos Nasales/inmunología , Receptores de Citocinas/genética , Receptores de Citocinas/inmunología , Factor de Transcripción STAT5/inmunología , Linfopoyetina del Estroma TímicoRESUMEN
BACKGROUND: Airway epithelial cells have a well-accepted role in the regulation of local inflammatory processes in allergic and innate defence responses. However, their role the pathophysiology of chronic rhinosinusitis with nasal polyps (CRSwNP) is unclear. The objective was to investigate whether potential differences in the mRNA expression profile of nasal epithelia from healthy individuals and from CRSwNP patients would shed new light on disease mechanisms. METHODS: Primary epithelial cells from nasal polyps of 24 affected individuals and from middle turbinates of 9 healthy controls were obtained using magnetic beat assisted isolation and were used for expression profiling using the Human Genome U133 Plus 2.0 Genechip Array. RESULTS: Multiple gene probes corresponding to 27 genes showed an aberrant expression profile in polyp epithelial cells compared to healthy controls. Most of these genes are linked to pathogenic mechanisms seen in neoplasm formation, including changes in cell-cell adhesion, metabolic processes, cell cycle control, and differentiation. Remarkably, our data additionally suggest a role for maternally expressed genes in the pathogenesis of CRSwNP and reveal two distinct states of polyp epithelium that could not be linked to the presence or absence of atopy in patients or to the level of eosinophilia or neutrophilia of the polyp. CONCLUSIONS: Our data suggest new roles for nasal epithelium in the pathogenesis of CRSwNP.
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Mucosa Nasal , Pólipos Nasales , Rinitis , Sinusitis , Enfermedad Crónica , Humanos , Mucosa Nasal/patología , Rinitis/patología , Sinusitis/patología , Cornetes NasalesAsunto(s)
Células Dendríticas/inmunología , Células Epiteliales/fisiología , Inflamación/inmunología , Enfermedades Inflamatorias del Intestino/inmunología , Rinitis/inmunología , Sinusitis/inmunología , Animales , Enfermedad Crónica , Humanos , Tolerancia Inmunológica , Inmunidad Mucosa , Inmunoglobulina A/metabolismo , Inmunoglobulina G/metabolismo , Receptores Fc/metabolismoRESUMEN
Allergic rhinitis, nonallergic rhinitis, and chronic rhinosinusitis are multifactorial upper airway diseases with high prevalence. Several genetic and environmental factors are proposed to predispose to the pathogenesis of the inflammatory upper airway diseases. Still, the molecular mechanisms leading toward the onset and progression of upper airway diseases are largely unknown. The upper airway epithelium has an important role in sensing the environment and regulating the inhaled air. As such, it links environmental insults to the host immunity. Human sinonasal epithelium serves as an excellent target for observing induced early-phase events, in vivo, and with a systems biological perspective. Actually, increasing number of investigations have provided evidence that altered homeostasis in the sinonasal epithelium might be important in the chronic upper airway inflammation.
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Mucosa Nasal/inmunología , Rinitis/inmunología , Sinusitis/inmunología , Animales , Enfermedad Crónica , Genómica , Humanos , Rinitis/epidemiología , Factores de Riesgo , Sinusitis/epidemiologíaRESUMEN
BACKGROUND: There are many forms of rhinitis. Patients are diagnosed with non-allergic rhinitis when anatomic, infectious and allergic aetiologies have been excluded. The symptoms, including nasal congestion, blockage or obstruction, clear rhinorrhoea, sneezing and, less frequently, nasal itching, can range from mild to debilitating. It affects between 25% and 50% of patients with rhinitis. Several medications are widely used in the treatment of non-allergic rhinitis, including oral and topical nasal antihistamines, intranasal and (rarely) systemic corticosteroids, and anticholinergics. Capsaicin, the active component of chili peppers, delivered intranasally, is considered a treatment option for non-allergic rhinitis. OBJECTIVES: To assess the effectiveness of capsaicin in the management of non-allergic rhinitis compared with no therapy, placebo or other topical or systemic medications, or two or more of the above therapies in combination, or different capsaicin regimens. SEARCH METHODS: We searched the Cochrane Ear, Nose and Throat Disorders Group Trials Register; the Cochrane Central Register of Controlled Trials (CENTRAL 2015, Issue 5); PubMed; EMBASE; CINAHL; Web of Science; Cambridge Scientific Abstracts; ICTRP and additional sources for published and unpublished trials. The date of the search was 24 June 2015. SELECTION CRITERIA: Randomised controlled trials in adult patients with non-allergic rhinitis comparing intranasal capsaicin with no therapy, placebo or other topical or systemic medications, or their combinations. DATA COLLECTION AND ANALYSIS: We used the standard methodological procedures expected by The Cochrane Collaboration. MAIN RESULTS: We included four studies (five publications) involving 302 participants with idiopathic non-allergic rhinitis. All the included studies described patients with moderately severe, idiopathic non-allergic rhinitis who were between the ages of 16 and 65. Studies had follow-up periods ranging from four to 38 weeks. The overall risk of bias in the studies was either high or unclear (two studies had overall high risk of bias, while two others had low to unclear risk of bias). Using the GRADE system we assessed the evidence as being of low to moderate quality. A meta-analysis was not possible, given lack of similarity of the reported outcomes.Two studies compared capsaicin with placebo. One study reported that capsaicin resulted in an improvement of overall nasal symptoms (a primary outcome) measured on a visual analogue scale (VAS) of 0 to 10. There was a mean difference (MD) of -3.34 (95% confidence interval (CI) -5.24 to -1.44), MD -3.73 (95% CI -5.45 to -2.01) and MD -3.52 (95% CI -5.55 to -1.48) at two, 12 and 36 weeks post-treatment, respectively. Another study reported that, compared to placebo, capsaicin (at 4 µg/puff) was more likely to produce overall symptom resolution (reduction in nasal blockage, sneezing/itching/coughing and nasal secretion measured with a daily record chart) at four weeks post-treatment (a primary outcome). The risk ratio (RR) was 3.17 (95% CI 1.38 to 7.29).One study compared capsaicin to budesonide (an intranasal corticosteroid). This study found that patients treated with capsaicin had a better overall symptom score compared to those treated with budesonide (MD 2.50, 95% CI 1.06 to 3.94, VAS of 0 to 10). However, there were no differences in the individual symptom scores for headache, postnasal drip, rhinorrhoea, nasal blockage, sneezing and sore throat assessed during the last three days of a four-week treatment.One study compared two different regimens of capsaicin administration: five treatments in one day versus five treatments given every two to three days during two weeks. Using daily record charts, the study reported significant improvement of individual symptom scores for rhinorrhoea in patients treated five times per day, however numerical data were not presented. There were no improvements in the other outcomes: rhinorrhoea, nasal obstruction, sneezing and overall nasal symptoms, measured on a VAS.Finally, one of these studies also compared three doses of capsaicin (to placebo). Patients treated with a 1 µg versus 4 µg per puff dose of capsaicin had a worse daily record chart overall symptom score resolution (RR 0.63, 95% CI 0.34 to 1.16).Only one study attempted to measure adverse effects (a primary outcome), however due to methodological issues with the assessment we are unable to draw any conclusions.We sought to include other secondary outcomes (e.g. quality of life measures, treatment dropouts, endoscopic scores, turbinate or mucosal size, cost of therapy), but none of these were measured or reported in the included studies. AUTHORS' CONCLUSIONS: Capsaicin may be an option in the treatment of idiopathic non-allergic rhinitis. It is given in the form of brief treatments, usually during the same day. It appears to have beneficial effects on overall nasal symptoms up to 36 weeks after treatment, based on a few, small studies (low-quality evidence). Well-conducted randomised controlled trials are required to further advance our understanding of the effectiveness of capsaicin in non-allergic rhinitis, especially in patients with non-allergic rhinitis of different types and severity, and using different methods of capsaicin application.
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Antiinflamatorios/uso terapéutico , Capsaicina/uso terapéutico , Rinitis/tratamiento farmacológico , Adolescente , Adulto , Anciano , Budesonida/uso terapéutico , Capsaicina/administración & dosificación , Humanos , Persona de Mediana Edad , Ensayos Clínicos Controlados Aleatorios como AsuntoRESUMEN
BACKGROUND: Rhinovirus infections are the most common cause of asthma exacerbations. The complex responses by airway epithelium to rhinovirus can be captured by gene expression profiling. We hypothesized that: a) upper and lower airway epithelium exhibit differential responses to double-stranded RNA (dsRNA), and b) that this is modulated by the presence of asthma and allergic rhinitis. OBJECTIVES: Identification of dsRNA-induced gene expression profiles of primary nasal and bronchial epithelial cells from the same individuals and examining the impact of allergic rhinitis with and without concomitant allergic asthma on expression profiles. METHODS: This study had a cross-sectional design including 18 subjects: 6 patients with allergic asthma with concomitant rhinitis, 6 patients with allergic rhinitis, and 6 healthy controls. Comparing 6 subjects per group, the estimated false discovery rate was approximately 5%. RNA was extracted from isolated and cultured primary epithelial cells from nasal biopsies and bronchial brushings stimulated with dsRNA (poly(I:C)), and analyzed by microarray (Affymetrix U133+ PM Genechip Array). Data were analysed using R and the Bioconductor Limma package. Overrepresentation of gene ontology groups were captured by GeneSpring GX12. RESULTS: In total, 17 subjects completed the study successfully (6 allergic asthma with rhinitis, 5 allergic rhinitis, 6 healthy controls). dsRNA-stimulated upper and lower airway epithelium from asthma patients demonstrated significantly fewer induced genes, exhibiting reduced down-regulation of mitochondrial genes. The majority of genes related to viral responses appeared to be similarly induced in upper and lower airways in all groups. However, the induction of several interferon-related genes (IRF3, IFNAR1, IFNB1, IFNGR1, IL28B) was impaired in patients with asthma. CONCLUSIONS: dsRNA differentially changes transcriptional profiles of primary nasal and bronchial epithelial cells from patients with allergic rhinitis with or without asthma and controls. Our data suggest that respiratory viruses affect mitochondrial genes, and we identified disease-specific genes that provide potential targets for drug development.
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Asma/genética , ARN Bicatenario/biosíntesis , ARN Bicatenario/genética , Mucosa Respiratoria/fisiología , Rinitis/genética , Transcriptoma/fisiología , Adulto , Asma/metabolismo , Asma/patología , Células Cultivadas , Estudios Transversales , Femenino , Humanos , Masculino , Cultivo Primario de Células , Rinitis/metabolismo , Rinitis/patología , Adulto JovenRESUMEN
Introduction: The coronavirus disease 2019 (COVID-19) pandemic has led to the death of almost 7 million people, however, with a cumulative incidence of 0.76 billion, most people survive COVID-19. Several studies indicate that the acute phase of COVID-19 may be followed by persistent symptoms including fatigue, dyspnea, headache, musculoskeletal symptoms, and pulmonary functional-and radiological abnormalities. However, the impact of COVID-19 on long-term health outcomes remains to be elucidated. Aims: The Precision Medicine for more Oxygen (P4O2) consortium COVID-19 extension aims to identify long COVID patients that are at risk for developing chronic lung disease and furthermore, to identify treatable traits and innovative personalized therapeutic strategies for prevention and treatment. This study aims to describe the study design and first results of the P4O2 COVID-19 cohort. Methods: The P4O2 COVID-19 study is a prospective multicenter cohort study that includes nested personalized counseling intervention trial. Patients, aged 40-65 years, were recruited from outpatient post-COVID clinics from five hospitals in The Netherlands. During study visits at 3-6 and 12-18 months post-COVID-19, data from medical records, pulmonary function tests, chest computed tomography scans and biological samples were collected and questionnaires were administered. Furthermore, exposome data was collected at the patient's home and state-of-the-art imaging techniques as well as multi-omics analyses will be performed on collected data. Results: 95 long COVID patients were enrolled between May 2021 and September 2022. The current study showed persistence of clinical symptoms and signs of pulmonary function test/radiological abnormalities in post-COVID patients at 3-6 months post-COVID. The most commonly reported symptoms included respiratory symptoms (78.9%), neurological symptoms (68.4%) and fatigue (67.4%). Female sex and infection with the Delta, compared with the Beta, SARS-CoV-2 variant were significantly associated with more persisting symptom categories. Conclusions: The P4O2 COVID-19 study contributes to our understanding of the long-term health impacts of COVID-19. Furthermore, P4O2 COVID-19 can lead to the identification of different phenotypes of long COVID patients, for example those that are at risk for developing chronic lung disease. Understanding the mechanisms behind the different phenotypes and identifying these patients at an early stage can help to develop and optimize prevention and treatment strategies.
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Chronic rhinosinusitis is a heterogeneous and multifactorial disease with unknown etiology. Aberrant responses to microorganisms have been suggested to play a role in the pathophysiology of the disease. Research has focused on the presence, detection, response to, and eradication of these potential threats. Main topics seem to center on the contribution of structural cells such as epithelium and fibroblasts, on the consequences of activation of pattern-recognition receptors, and on the role of antimicrobial agents. This research should be viewed not only in the light of a comparison between healthy and diseased individuals, but also in a comparison between patients who do or do not respond to treatment. New players that could play a role in the pathophysiology seem to surface at regular intervals, adding to our understanding (and the complexity) of the disease and opening new avenues that may help fight this incapacitating disease.
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Bacterias/aislamiento & purificación , Hongos/aislamiento & purificación , Rinitis/inmunología , Rinitis/microbiología , Sinusitis/inmunología , Sinusitis/microbiología , Antiinfecciosos/uso terapéutico , Enfermedad Crónica , Epitelio/inmunología , Fibroblastos/inmunología , Humanos , Inmunidad Innata , Polimorfismo Genético , Receptores de Reconocimiento de Patrones/inmunología , Rinitis/genética , Rinitis/terapia , Sinusitis/genética , Sinusitis/terapiaRESUMEN
Cystic fibrosis is caused by genetic defects that impair the CFTR channel in airway epithelial cells. These defects may be overcome by specific CFTR modulating drugs, for which the efficacy can be predicted in a personalized manner using 3D nasal-brushing-derived airway organoids in a forskolin-induced swelling assay. Despite of this, previously described CFTR function assays in 3D airway organoids were not fully optimal, because of inefficient organoid differentiation and limited scalability. In this report, we therefore describe an alternative method of culturing nasal-brushing-derived airway organoids, which are created from an equally differentiated airway epithelial monolayer of a 2D air-liquid interface culture. In addition, we have defined organoid culture conditions, with the growth factor/cytokine combination neuregulin-1<i>ß</i> and interleukin-1<i>ß</i>, which enabled consistent detection of CFTR modulator responses in nasal-airway organoid cultures from subjects with cystic fibrosis.
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Fibrosis Quística , Células Cultivadas , Fibrosis Quística/genética , Regulador de Conductancia de Transmembrana de Fibrosis Quística/genética , Células Epiteliales , Humanos , OrganoidesRESUMEN
Group 2 innate lymphoid cells (ILC2s) orchestrate protective type 2 immunity and have been implicated in various immune disorders. In the mouse, circulatory inflammatory ILC2s (iILC2s) were identified as a major source of type 2 cytokines. The human equivalent of the iILC2 subset remains unknown. Here, we identify a human inflammatory ILC2 population that resides in inflamed mucosal tissue and is specifically marked by surface CD45RO expression. CD45RO+ ILC2s are derived from resting CD45RA+ ILC2s upon activation by epithelial alarmins such as IL-33 and TSLP, which is tightly linked to STAT5 activation and up-regulation of the IRF4/BATF transcription factors. Transcriptome analysis reveals marked similarities between human CD45RO+ ILC2s and mouse iILC2s. Frequencies of CD45RO+ inflammatory ILC2 are increased in inflamed mucosal tissue and in the circulation of patients with chronic rhinosinusitis or asthma, correlating with disease severity and resistance to corticosteroid therapy. CD45RA-to-CD45RO ILC2 conversion is suppressed by corticosteroids via induction of differentiation toward an immunomodulatory ILC2 phenotype characterized by low type 2 cytokine and high amphiregulin expression. Once converted, however, CD45RO+ ILC2s are resistant to corticosteroids, which is associated with metabolic reprogramming resulting in the activation of detoxification pathways. Our combined data identify CD45RO+ inflammatory ILC2s as a human analog of mouse iILC2s linked to severe type 2 inflammatory disease and therapy resistance.
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Asma/tratamiento farmacológico , Glucocorticoides/farmacología , Antígenos Comunes de Leucocito/metabolismo , Linfocitos/inmunología , Pólipos Nasales/tratamiento farmacológico , Adolescente , Adulto , Anciano , Asma/diagnóstico , Asma/inmunología , Resistencia a Medicamentos/inmunología , Femenino , Glucocorticoides/uso terapéutico , Humanos , Inmunidad Innata , Linfocitos/metabolismo , Masculino , Persona de Mediana Edad , Pólipos Nasales/inmunología , Índice de Severidad de la Enfermedad , Adulto JovenRESUMEN
Patients diagnosed with coronavirus disease 2019 (COVID-19) become critically ill primarily around the time of activation of the adaptive immune response. Here, we provide evidence that antibodies play a role in the worsening of disease at the time of seroconversion. We show that early-phase severe acute respiratory distress syndrome coronavirus 2 (SARS-CoV-2) spike protein-specific immunoglobulin G (IgG) in serum of critically ill COVID-19 patients induces excessive inflammatory responses by human alveolar macrophages. We identified that this excessive inflammatory response is dependent on two antibody features that are specific for patients with severe COVID-19. First, inflammation is driven by high titers of anti-spike IgG, a hallmark of severe disease. Second, we found that anti-spike IgG from patients with severe COVID-19 is intrinsically more proinflammatory because of different glycosylation, particularly low fucosylation, of the antibody Fc tail. Low fucosylation of anti-spike IgG was normalized in a few weeks after initial infection with SARS-CoV-2, indicating that the increased antibody-dependent inflammation mainly occurs at the time of seroconversion. We identified Fcγ receptor (FcγR) IIa and FcγRIII as the two primary IgG receptors that are responsible for the induction of key COVID-19-associated cytokines such as interleukin-6 and tumor necrosis factor. In addition, we show that anti-spike IgG-activated human macrophages can subsequently break pulmonary endothelial barrier integrity and induce microvascular thrombosis in vitro. Last, we demonstrate that the inflammatory response induced by anti-spike IgG can be specifically counteracted by fostamatinib, an FDA- and EMA-approved therapeutic small-molecule inhibitor of Syk kinase.
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Anticuerpos Antivirales/química , COVID-19/inmunología , Inmunoglobulina G/química , Macrófagos Alveolares/inmunología , Glicosilación , Humanos , Inflamación , SARS-CoV-2 , Glicoproteína de la Espiga del Coronavirus/inmunologíaRESUMEN
INTRODUCTION: Severe asthma is a rare disease in children, for which three biologicals, anti-immunoglobulin E, anti-interleukin-5 and anti-IL4RA antibodies, are available in European countries. While global guidelines exist on who should receive biologicals, knowledge is lacking on how those guidelines are implemented in real life and which unmet needs exist in the field. In this survey, we aimed to investigate the status quo and identify open questions in biological therapy of childhood asthma across Europe. METHODS: Structured interviews regarding experience with biologicals, regulations on access to the different treatment options, drug selection, therapy success and discontinuation of therapy were performed. Content analysis was used to analyse data. RESULTS: We interviewed 37 experts from 25 European countries and Turkey and found a considerable range in the number of children treated with biologicals per centre. All participating countries provide public access to at least one biological. Most countries allow different medical disciplines to prescribe biologicals to children with asthma, and only a few restrict therapy to specialised centres. We observed significant variation in the time point at which treatment success is assessed, in therapy duration and in the success rate of discontinuation. Most participating centres intend to apply a personalised medicine approach in the future to match patients a priori to available biologicals. CONCLUSION: Substantial differences exist in the management of childhood severe asthma across Europe, and the need for further studies on biomarkers supporting selection of biologicals, on criteria to assess therapy response and on how/when to end therapy in stable patients is evident.
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BACKGROUND: Dendritic cells (DC) linking innate and adaptive immune responses are present in human lungs, but the characterization of different subsets and their role in COPD pathogenesis remain to be elucidated. The aim of this study is to characterize and quantify pulmonary myeloid DC subsets in small airways of current and ex-smokers with or without COPD. METHODS: Myeloid DC were characterized using flowcytometry on single cell suspensions of digested human lung tissue. Immunohistochemical staining for langerin, BDCA-1, CD1a and DC-SIGN was performed on surgical resection specimens from 85 patients. Expression of factors inducing Langerhans-type DC (LDC) differentiation was evaluated by RT-PCR on total lung RNA. RESULTS: Two segregated subsets of tissue resident pulmonary myeloid DC were identified in single cell suspensions by flowcytometry: the langerin+ LDC and the DC-SIGN+ interstitial-type DC (intDC). LDC partially expressed the markers CD1a and BDCA-1, which are also present on their known blood precursors. In contrast, intDC did not express langerin, CD1a or BDCA-1, but were more closely related to monocytes.Quantification of DC in the small airways by immunohistochemistry revealed a higher number of LDC in current smokers without COPD and in COPD patients compared to never smokers and ex-smokers without COPD. Importantly, there was no difference in the number of LDC between current and ex-smoking COPD patients.In contrast, the number of intDC did not differ between study groups. Interestingly, the number of BDCA-1+ DC was significantly lower in COPD patients compared to never smokers and further decreased with the severity of the disease. In addition, the accumulation of LDC in the small airways significantly correlated with the expression of the LDC inducing differentiation factor activin-A. CONCLUSIONS: Myeloid DC differentiation is altered in small airways of current smokers and COPD patients resulting in a selective accumulation of the LDC subset which correlates with the pulmonary expression of the LDC-inducing differentiation factor activin-A. This study identified the LDC subset as an interesting focus for future research in COPD pathogenesis.
Asunto(s)
Células de Langerhans/inmunología , Pulmón/inmunología , Enfermedad Pulmonar Obstructiva Crónica/inmunología , Fumar/inmunología , Activinas/genética , Anciano , Antígenos CD/análisis , Antígenos CD1/análisis , Antígenos de Superficie/análisis , Moléculas de Adhesión Celular/análisis , Diferenciación Celular , Femenino , Citometría de Flujo , Glicoproteínas , Humanos , Inmunohistoquímica , Interleucina-15/genética , Péptidos y Proteínas de Señalización Intracelular , Lectinas Tipo C/análisis , Modelos Lineales , Pulmón/fisiopatología , Masculino , Lectinas de Unión a Manosa/análisis , Proteínas de la Membrana/genética , Persona de Mediana Edad , Enfermedad Pulmonar Obstructiva Crónica/genética , Enfermedad Pulmonar Obstructiva Crónica/fisiopatología , Ligando RANK/genética , ARN Mensajero/análisis , Receptores de Superficie Celular/análisis , Reacción en Cadena de la Polimerasa de Transcriptasa Inversa , Fumar/efectos adversos , Fumar/genética , Cese del Hábito de FumarRESUMEN
PURPOSE OF REVIEW: Childhood asthma is a heterogeneous inflammatory disease comprising different phenotypes and endotypes and, particularly in its severe forms, has a large impact on the quality-of-life of patients and caregivers. The application of advanced omics technologies provides useful insights into underlying asthma endotypes and may provide potential clinical biomarkers to guide treatment and move towards a precision medicine approach. RECENT FINDINGS: The current article addresses how novel omics approaches have shaped our current understanding of childhood asthma and highlights recent findings from (pharmaco)genomics, epigenomics, transcriptomics, and metabolomics studies on childhood asthma and their potential clinical implications to guide treatment in severe asthmatics. SUMMARY: Until now, omics studies have largely expanded our view on asthma heterogeneity, helped understand cellular processes underlying asthma, and brought us closer towards identifying (bio)markers that will allow the prediction of treatment responsiveness and disease progression. There is a clinical need for biomarkers that will guide treatment at the individual level, particularly in the field of biologicals. The integration of multiomics data together with clinical data could be the next promising step towards development individual risk prediction models to guide treatment. However, this requires large-scale collaboration in a multidisciplinary setting.
Asunto(s)
Antiasmáticos/uso terapéutico , Asma/diagnóstico , Productos Biológicos/uso terapéutico , Medicina de Precisión/métodos , Antiasmáticos/farmacología , Asma/tratamiento farmacológico , Asma/genética , Asma/inmunología , Productos Biológicos/farmacología , Biomarcadores/análisis , Niño , Progresión de la Enfermedad , Epigenómica/métodos , Epigenómica/tendencias , Perfilación de la Expresión Génica/tendencias , Predisposición Genética a la Enfermedad , Humanos , Metabolómica/métodos , Metabolómica/tendencias , Pruebas de Farmacogenómica/métodos , Pruebas de Farmacogenómica/tendencias , Medicina de Precisión/tendencias , Proteómica/métodos , Proteómica/tendencias , Índice de Severidad de la Enfermedad , Resultado del TratamientoRESUMEN
The aim of this study was to compare the efficacy and patient discomfort between four techniques for obtaining nasal secretions. Nasal secretions from 58 patients with symptoms of a common cold, from three clinical centers (Amsterdam, Lodz, Oslo), were obtained by four different methods: swab, aspirate, brush, and wash. In each patient all four sampling procedures were performed and patient discomfort was evaluated by a visual discomfort scale (scale 1-5) after each procedure. Single pathogen RT-PCRs for Rhinovirus (RV), Influenza virus and Adenovirus, and multiplex real-time PCR for RV, Enterovirus, Influenza virus, Adenovirus, Respiratory Syncytial Virus (RSV), Parainfluenza virus, Coronavirus, Metapneumovirus, Bocavirus and Parechovirus were performed in all samples. A specific viral cause of respiratory tract infection was determined in 48 patients (83%). In these, the detection rate for any virus was 88% (wash), 79% (aspirate), 77% (swab) and 74% (brush). The degree of discomfort reported was 2.54 for swabs, 2.63 for washes, 2.68 for aspirates and 3.61 for brushings. Nasal washes yielded the highest rate of viral detection without excessive patient discomfort. In contrast, nasal brushes produced the lowest detection rates and demonstrated the highest level of discomfort.