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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 , Criança , Humanos , DisbioseRESUMO
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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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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Fibrose Cística , Células Cultivadas , Fibrose Cística/genética , Regulador de Condutância Transmembrana em Fibrose Cística/genética , Células Epiteliais , Humanos , OrganoidesRESUMO
A digital multidisciplinary European expert meeting took place on the 9 July 2020 to identify the unmet needs of paediatric severe asthma patients, and set the priorities for clinical and research activities ahead https://bit.ly/3CeLBHB.
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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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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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Anticorpos Antivirais/química , COVID-19/imunologia , Imunoglobulina G/química , Macrófagos Alveolares/imunologia , Glicosilação , Humanos , Inflamação , SARS-CoV-2 , Glicoproteína da Espícula de Coronavírus/imunologiaRESUMO
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/tratamento farmacológico , Glucocorticoides/farmacologia , Antígenos Comuns de Leucócito/metabolismo , Linfócitos/imunologia , Pólipos Nasais/tratamento farmacológico , Adolescente , Adulto , Idoso , Asma/diagnóstico , Asma/imunologia , Resistência a Medicamentos/imunologia , Feminino , Glucocorticoides/uso terapêutico , Humanos , Imunidade Inata , Linfócitos/metabolismo , Masculino , Pessoa de Meia-Idade , Pólipos Nasais/imunologia , Índice de Gravidade de Doença , Adulto JovemRESUMO
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 , Linfócitos/imunologia , Rinite Alérgica Sazonal/imunologia , Imunoterapia Sublingual/métodos , Adulto , Alérgenos/imunologia , Método Duplo-Cego , Feminino , Humanos , Tolerância Imunológica , Imunidade Inata , Janus Quinases/metabolismo , Lectinas Tipo C/metabolismo , Masculino , Pessoa de Meia-Idade , Efeito Placebo , Poaceae/imunologia , Pólen/imunologia , Receptores Imunológicos/metabolismo , Rinite Alérgica Sazonal/terapia , Fatores de Transcrição STAT/metabolismo , Transdução de Sinais , Células Th2/imunologia , Resultado do Tratamento , Vitamina A/metabolismo , Adulto JovemAssuntos
Células Dendríticas/imunologia , Células Epiteliais/fisiologia , Inflamação/imunologia , Doenças Inflamatórias Intestinais/imunologia , Rinite/imunologia , Sinusite/imunologia , Animais , Doença Crônica , Humanos , Tolerância Imunológica , Imunidade nas Mucosas , Imunoglobulina A/metabolismo , Imunoglobulina G/metabolismo , Receptores Fc/metabolismoRESUMO
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.
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Antiasmáticos/uso terapêutico , Asma/diagnóstico , Produtos Biológicos/uso terapêutico , Medicina de Precisão/métodos , Antiasmáticos/farmacologia , Asma/tratamento farmacológico , Asma/genética , Asma/imunologia , Produtos Biológicos/farmacologia , Biomarcadores/análise , Criança , Progressão da Doença , Epigenômica/métodos , Epigenômica/tendências , Perfilação da Expressão Gênica/tendências , Predisposição Genética para Doença , Humanos , Metabolômica/métodos , Metabolômica/tendências , Testes Farmacogenômicos/métodos , Testes Farmacogenômicos/tendências , Medicina de Precisão/tendências , Proteômica/métodos , Proteômica/tendências , Índice de Gravidade de Doença , Resultado do TratamentoRESUMO
Innate lymphoid cells (ILCs) are crucial for the immune surveillance at mucosal sites. ILCs coordinate early eradication of pathogens and contribute to tissue healing and remodeling, features that are dysfunctional in patients with cystic fibrosis (CF). The mechanisms by which ILCs contribute to CF-immunopathology are ill-defined. Here, we show that group 2 ILCs (ILC2s) transdifferentiated into IL-17-secreting cells in the presence of the epithelial-derived cytokines IL-1ß, IL-23 and TGF-ß. This conversion is abrogated by IL-4 or vitamin D3. IL-17 producing ILC2s induce IL-8 secretion by epithelial cells and their presence in nasal polyps of CF patients is associated with neutrophilia. Our data suggest that ILC2s undergo transdifferentiation in CF nasal polyps in response to local cytokines, which are induced by infectious agents.
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Plasticidade Celular/imunologia , Fibrose Cística/imunologia , Inflamação/imunologia , Pólipos Nasais/imunologia , Células Th17/imunologia , Adulto , Animais , Linhagem Celular , Fibrose Cística/sangue , Fibrose Cística/patologia , Feminino , Humanos , Imunidade Inata , Inflamação/sangue , Inflamação/patologia , Interleucina-17/imunologia , Interleucina-17/metabolismo , Interleucina-1beta/imunologia , Interleucina-1beta/metabolismo , Interleucina-23/imunologia , Interleucina-23/metabolismo , Masculino , Camundongos , Pessoa de Meia-Idade , Mucosa Nasal/citologia , Mucosa Nasal/imunologia , Mucosa Nasal/patologia , Pólipos Nasais/sangue , Pólipos Nasais/patologia , Neutrófilos/imunologia , Adulto JovemRESUMO
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 Nasais , Rinite , Sinusite , Doença Crônica , Humanos , Mucosa Nasal/patologia , Rinite/patologia , Sinusite/patologia , Conchas NasaisRESUMO
BACKGROUND: Endotyping chronic rhinitis has proven hardest for the subgroup of non-allergic rhinitis (NAR) patients. While IgE-related inflammation is typical for allergic rhinitis (AR), no markers have been found that can be seen to positively identify NAR. A further complication is that AR and NAR might co-exist in patients with mixed rhinitis. As previous studies have considered only a limited number of inflammatory mediators, we wanted to explore whether a wider panel of mediators could help us refine the endotyping in chronic rhinitis patients. OBJECTIVE: To endotype chronic rhinitis, and non-allergic rhinitis in particular, with help of molecular or cellular markers. METHOD: In this study we included 23 NAR patients without allergen sensitizations and with persistent rhinitis symptoms, 22 pollen sensitized rhinitis patients with seasonal symptoms, 21 mixed rhinitis patients with pollen-related symptoms and persistent symptoms outside of the pollen season, and 23 healthy controls without any symptoms. Nasal secretions were collected outside of pollen season and differences between the endotypes were assessed for a broad range of inflammatory mediators and growths factors using a multiplex ELISA. RESULTS: Although we were able to identify two new nasal secretion makers (IL-12 and HGF) that were low in mixed and AR patients versus NAR and healthy controls, the most intriguing outcome is that despite investigating 29 general inflammatory mediators and growth factors no clear profile of non-allergic or mixed rhinitis could be found. CONCLUSION: Classical inflammatory markers are not able to differentiate between non-allergic or mixed rhinitis patients and healthy controls.
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Mucosa Nasal/metabolismo , Rinite/metabolismo , Adulto , Biomarcadores/metabolismo , Doença Crônica , Feminino , Fator de Crescimento de Hepatócito/metabolismo , Humanos , Interleucina-12/metabolismo , Masculino , Hipersensibilidade Respiratória/metabolismoRESUMO
BACKGROUND: This study was conducted to assess the effect of comorbidity, ethnicity, occupation, smoking and place of residence on allergic rhinitis (AR), acute rhinosinusitis (ARS) and chronic rhinosinusitis (CRS). METHODS: A GA2LEN (The Global Allergy and Asthma European Network) screening questionnaire was sent to a random sample of the Dutch population (n = 16700) in three different areas of the Netherlands. RESULTS: Fifty percent (8347) of the questionnaires sent were returned. A total of 29% respondents (27-31% in different areas) met the criteria for AR, 18% (17-21%) for ARS and 16% (13-18%) for CRS. Risk factors for AR were itchy rash, eczema, adverse response after taking a painkiller, asthma, CRS and ARS. Moreover, the risk of AR was twice as low for full-time housewives/househusbands than for people with jobs. The risk of ARS or CRS was significantly higher in respondents with a doctor's diagnosis of CRS, AR, itchy rash or smoking. The risk of CRS was also significantly higher in respondents with an adverse response after taking painkillers, active smoking or asthma. Caucasians are generally less likely to have AR or CRS than Latin-Americans, Hindustani and African-Creoles, and more likely to have ARS than Asian, Hindustani, Mediterranean and African-Creoles. CONCLUSIONS: This study found shared and distinct risk factors for AR, ARS and CRS and therefore provides support for the belief that they have shared symptoms but are different diseases with different aetiologies.
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Rinite Alérgica/epidemiologia , Sinusite/epidemiologia , Doença Aguda , Adulto , Doença Crônica , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Análise Multivariada , Rinite Alérgica/complicações , Rinite Alérgica/etnologia , Sinusite/complicações , Sinusite/etnologia , Inquéritos e QuestionáriosRESUMO
Immunohistochemistry was used to identify, enumerate, and describe the tissue distribution of Langerhans type (CD1a and CD207), myeloid (CD1c and CD141), and plasmacytoid (CD303 and CD304) dendritic cell subsets in oral mucosa of allergic and non-allergic individuals. Allergic individuals have more CD141+ myeloid cells in epithelium and more CD1a+ Langerhans cells in the lamina propria compared to healthy controls, but similar numbers for the other DC subtypes. Our data are the first to describe the presence of CD303+ plasmacytoid DCs in human oral mucosa and a dense intraepithelial network of CD141+ DCs. The number of Langerhans type DCs (CD1a and CD207) and myeloid DCs (CD1c), was higher in the oral mucosa than in the nasal mucosa of the same individual independent of the atopic status.
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Células Dendríticas/patologia , Voluntários Saudáveis , Hipersensibilidade/patologia , Mucosa Bucal/patologia , Adolescente , Adulto , Estudos de Casos e Controles , Contagem de Células , Feminino , Humanos , Imuno-Histoquímica , Masculino , Pessoa de Meia-Idade , Mucosa Nasal/patologia , Adulto JovemRESUMO
INTRODUCTION: Chronic rhinosinusitis with nasal polyposis is an inflammatory disease that, although not directly linked to allergy, often displays a Th2-skewed inflammation characterized by elevated local IgE and IL-5 levels. The nasal cavity is constantly exposed to bacteria and viruses that may trigger epithelial inflammatory responses. To gain more insight into mechanisms by which such a biased inflammation might arise, we have investigated the epithelial expression of the Th2 skewing mediators (TSLP, IL-25, and IL-33) in relationship to disease and microbial triggers. METHODS: Epithelial cells were obtained from polyp tissues of nasal polyposis patients and from inferior turbinates of non-diseased controls. Cells were exposed to various TLR-specific triggers to study the effect on mRNA and protein expression level of TSLP, IL-25, and IL-33 and the potential regulatory mechanisms through the expression profile the transcription factors ATF-3, DUSP-1, EGR-1, and NFKB-1. RESULTS: The TLR3 agonist and viral analogue poly(I:C) induced TSLP mRNA 13.0 ± 3.1 fold (p < 0.05) and protein expression by 12.1 ± 2.3-fold (p < 0.05) higher in epithelium isolated from nasal polyposis patients than in epithelium form healthy controls. This enhanced induction of TSLP may be a consequence of a down-regulated expression of DUSP-1 in polyp epithelium. CONCLUSION: The TLR3 induced expression of TSLP introduces a mechanism by which the Th2-skewed tissue environment might arise in nasal polyps and invites a further evaluation of the potential contribution of current or past viral infections to polyposis pathogenesis.
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Citocinas/biossíntese , Pólipos Nasais/metabolismo , Poli I-C/metabolismo , RNA Viral/fisiologia , Humanos , Pólipos Nasais/patologia , Linfopoietina do Estroma do TimoRESUMO
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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Plasticidade Celular , Eosinófilos/imunologia , Imunidade Inata , Interleucina-12/metabolismo , Interleucina-1beta/metabolismo , Interleucina-4/metabolismo , Linfócitos/imunologia , Pólipos Nasais/imunologia , Pneumonia/imunologia , Doença Pulmonar Obstrutiva Crônica/imunologia , Rinite/imunologia , Sinusite/imunologia , Animais , Diferenciação Celular , Células Cultivadas , Feminino , Humanos , Interferon gama/metabolismo , Ativação Linfocitária , Camundongos , Camundongos SCID , Células Th1/imunologia , Equilíbrio Th1-Th2 , Células Th2/imunologiaRESUMO
BACKGROUND: Current phenotyping of chronic rhinosinusitis (CRS) into chronic rhinosinusitis with nasal polyps (CRSwNP) and chronic rhinosinusitis without nasal polyps (CRSsNP) might not adequately reflect the pathophysiologic diversity within patients with CRS. OBJECTIVE: We sought to identify inflammatory endotypes of CRS. Therefore we aimed to cluster patients with CRS based solely on immune markers in a phenotype-free approach. Secondarily, we aimed to match clusters to phenotypes. METHODS: In this multicenter case-control study patients with CRS and control subjects underwent surgery, and tissue was analyzed for IL-5, IFN-γ, IL-17A, TNF-α, IL-22, IL-1ß, IL-6, IL-8, eosinophilic cationic protein, myeloperoxidase, TGF-ß1, IgE, Staphylococcus aureus enterotoxin-specific IgE, and albumin. We used partition-based clustering. RESULTS: Clustering of 173 cases resulted in 10 clusters, of which 4 clusters with low or undetectable IL-5, eosinophilic cationic protein, IgE, and albumin concentrations, and 6 clusters with high concentrations of those markers. The group of IL-5-negative clusters, 3 clusters clinically resembled a predominant chronic rhinosinusitis without nasal polyps (CRSsNP) phenotype without increased asthma prevalence, and 1 cluster had a TH17 profile and had mixed CRSsNP/CRSwNP. The IL-5-positive clusters were divided into a group with moderate IL-5 concentrations, a mixed CRSsNP/CRSwNP and increased asthma phenotype, and a group with high IL-5 levels, an almost exclusive nasal polyp phenotype with strongly increased asthma prevalence. In the latter group, 2 clusters demonstrated the highest concentrations of IgE and asthma prevalence, with all samples expressing Staphylococcus aureus enterotoxin-specific IgE. CONCLUSION: Distinct CRS clusters with diverse inflammatory mechanisms largely correlated with phenotypes and further differentiated them and provided a more accurate description of the inflammatory mechanisms involved than phenotype information only.