Pulmonary exacerbations in early cystic fibrosis lung disease are marked by strong modulation of CD3 and PD-1 on luminal T cells

BackgroundIn chronic cystic fibrosis (CF) lung disease, neutrophilic inflammation and T-cell inhibition occur concomitantly, partly due to neutrophil-mediated release of the T-cell inhibitory enzyme Arg1. However, the onset of this tonic inhibition of T cells, and the impact of pulmonary exacerbations (PEs) on this process, remain unknown.MethodsChildren with CF aged 0-5 years were enrolled in a longitudinal, single-center cohort study. Blood (n = 35) and bronchoalveolar lavage (BAL) fluid (n = 18) were collected at stable outpatient clinic visits or inpatient PE hospitalizations and analyzed by flow cytometry (for immune cell presence and phenotype) and 20-plex chemiluminescence assay (for immune mediators). Patients were categorized by PE history into (i) no prior PE, (ii) past history of PE prior to stable visit, or (iii) current PE.ResultsPEs were associated with increased concentration of both pro- and anti-inflammatory mediators in BAL, and increased neutrophil frequency and G-CSF in circulation. PE BAL samples showed a trend toward an increased frequency of hyperexocytic “GRIM” neutrophils, which we previously identified in chronic CF. Interestingly, expression levels of the T-cell receptor associated molecule CD3 and of the inhibitory programmed death-1 (PD-1) receptor were respectively decreased and increased on T cells from BAL compared to blood in all patients. When categorized by PE status, CD3 and PD-1 expression on blood T cells did not differ among patients, while CD3 expression was decreased, and PD-1 expression was increased on BAL T cells from patients with current PE.ConclusionsOur findings suggest that airway T cells are engaged during early-life PEs, prior to the onset of chronic neutrophilic inflammation in CF. In addition, increased blood neutrophil frequency and a trend toward increased BAL frequency of hyperexocytic neutrophils suggest that childhood PEs may progressively shift the balance of CF airway immunity towards neutrophil dominance

Blood basophils from cystic fibrosis patients with allergic bronchopulmonary aspergillosis are primed and hyper-responsive to stimulation by aspergillus allergens

AbstractIntroductionFifteen to sixty percent of cystic fibrosis patients harbor Aspergillus fumigatus (Af) in their airways (CF-AC) and some will develop allergic bronchopulmonary aspergillosis (CF-ABPA). Since basophils play a key role in allergy, we hypothesized that they would display alterations in CF-ABPA patients compared to CF-AC or patients without Af colonization (CF).MethodsUsing flow cytometry, we measured CD203c, CD63 and CD123 levels on basophils from CF-ABPA (N=11), CF-AC (N=14), and CF (N=12) patients before and after ex vivo stimulation with Af allergens.ResultsBaseline CD203c was increased in basophils from CF-ABPA compared to CF-AC and CF patients. Af extract and recombinant Aspf1 stimulated basophils from CF-ABPA patients to markedly upregulate CD203c, along with modest upregulation of CD63 and a CD123 downward trend. Plasma TARC/CCL17 at baseline and post-stimulation cell supernatant histamine levels were similar in the three groups.ConclusionsIn CF-ABPA, blood basophils are primed and hyperresponsive to Af allergen stimulation

Airway macrophages display decreased expression of receptors mediating and regulating scavenging in early cystic fibrosis lung disease

Background: Cystic fibrosis (CF) airway disease is characterized by chronic inflammation, featuring neutrophil influx to the lumen. Airway macrophages (AMs) can promote both inflammation and resolution, and are thus critical to maintaining and restoring homeostasis. CF AM functions, specifically scavenging activity and resolution of inflammation, have been shown to be impaired, yet underlying processes remain unknown. We hypothesized that impaired CF AM function results from an altered expression of receptors that mediate or regulate scavenging, and set out to investigate changes in expression of these markers during the early stages of CF lung disease. Methods: Bronchoalveolar lavage fluid (BALF) was collected from 50 children with CF aged 1, 3 or 5 years. BALF cells were analyzed using flow cytometry. Expression levels of surface markers on AMs were expressed as median fluorescence intensities (MFI) or percentage of AMs positive for these markers. The effect of age and neutrophilic inflammation, among other variables, on marker expression was assessed with a multivariate linear regression model.Results: AM expression of scavenger receptor CD163 decreased with age (p = 0.016) and was negatively correlated with BALF %neutrophils (r = -0.34, p = 0.016). AM expression of immune checkpoint molecule SIRPα also decreased with age (p = 0.0006), but did not correlate with BALF %neutrophils. Percentage of AMs expressing lipid scavenger CD36 was low overall (mean 20.1% ± 16.5) and did not correlate with other factors. Conversely, expression of immune checkpoint PD-1 was observed on the majority of AMs (mean PD-1pos 72.9% ± 11.8), but it, too, was not affected by age or BALF %neutrophils. Compared to matched blood monocytes, AMs had a higher expression of CD16, CD91, and PD-1, and a lower expression of CD163, SIRPα and CD36. Conclusion: In BALF of preschool children with CF, higher age and/or increased neutrophilic inflammation coincided with decreased expression of scavenger receptors on AMs. Expression of scavenging receptors and regulators showed a distinctly different pattern in AMs compared to blood monocytes. These findings suggest AM capacity to counter inflammation and promote homeostasis reduces during initiation of CF airway disease and highlight new avenues of investigation into impaired CF AM function.</p

La mucoviscidose : une maladie complexe et un paradigme pour la recherche biomédicale

La mucoviscidose est une maladie génétique souvent fatale affectant les organes exocrines (tractus respiratoire, digestif, génital et cutané) et particulièrement fréquente dans la population d’Europe du Nord et d’Amérique du Nord. Pour pionnière qu’elle soit dans des secteurs aussi variés que la génétique, la physiologie, ou la pharmacologie, la recherche sur la mucoviscidose se heurte néanmoins, aujourd’hui encore, à d’importantes zones d’ombre. En particulier, les facteurs responsables du déclenchement et de la sévérité de l’atteinte respiratoire dans la mucoviscidose restent mal identifiés. L’objet de cette revue est non seulement de faire le point des connaissances actuelles et sur les processus physiopathologiques associés à la maladie, mais aussi de rendre compte des hypothèses non encore éclaircies et des modèles expérimentaux à disposition pour les explorer. Nous effectuerons enfin un survol rapide des solutions thérapeutiques novatrices issues des dernières années de recherche (thérapie génique et protéique) qui suscitent attente et espoirs chez les patients

Rabindra Tirouvanziam: Coronavirus infection of human lung epithelium and leukocytes: mechanisms and treatment

This presentation was made by Rabindra Tirouvanziam, Emory University. The presentation’s title is: Coronavirus infection of human lung epithelium and leukocytes: mechanisms and treatment.” Funded by NSF Engineering / Division of Chemical, Bioengineering, Environmental & Transport Systems. -- Every month, the COVID Information Commons Team (along with the Northeast Big Data Innovation Hub) brings together a group of researchers studying wide-ranging aspects of the current pandemic, to share their research and answer questions from our community. The events showcase scientists' ongoing efforts in the fight against COVID-19, including opportunities for collaboration

Rabindra Tirouvanziam: Infección por coronavirus del epitelio pulmonar humano y leucocitos: mecanismos y tratamiento

Descripción de esta presentación: Esta presentación fue realizada por Rabindra Tirouvanziam, Emory University. El título de la presentación es: "Infección por coronavirus del epitelio pulmonar humano y leucocitos: mecanismos y tratamiento". - Descripción de los seminarios web del CIC: Cada mes, el equipo de Information Commons de COVID (junto con el Northeast Big Data Innovation Hub) reúne a un grupo de investigadores que estudian diversos aspectos de la pandemia actual, para compartir sus investigaciones y responder preguntas de nuestra comunidad. Los eventos muestran los esfuerzos continuos de los científicos en la lucha contra el COVID-19, incluyendo oportunidades de colaboración

Neutrophil Adaptations upon Recruitment to the Lung: New Concepts and Implications for Homeostasis and Disease

Neutrophils have a prominent role in all human immune responses against any type of pathogen or stimulus. The lungs are a major neutrophil reservoir and neutrophilic inflammation is a primary response to both infectious and non-infectious challenges. While neutrophils are well known for their essential role in clearance of bacteria, they are also equipped with specific mechanisms to counter viruses and fungi. When these defense mechanisms become aberrantly activated in the absence of infection, this commonly results in debilitating chronic lung inflammation. Clearance of bacteria by phagocytosis is the hallmark role of neutrophils and has been studied extensively. New studies on neutrophil biology have revealed that this leukocyte subset is highly adaptable and fulfills diverse roles. Of special interest is how these adaptations can impact the outcome of an immune response in the lungs due to their potent capacity for clearing infection and causing damage to host tissue. The adaptability of neutrophils and their propensity to influence the outcome of immune responses implicates them as a much-needed target of future immunomodulatory therapies. This review highlights the recent advances elucidating the mechanisms of neutrophilic inflammation, with a focus on the lung environment due to the immense and growing public health burden of chronic lung diseases such as cystic fibrosis (CF) and chronic obstructive pulmonary disease (COPD), and acute lung inflammatory diseases such as transfusion-related acute lung injury (TRALI)