Abstract
BackgroundPulmonary sarcoidosis is an inflammatory disease characterised by granuloma formation and heterogeneous clinical outcome. Tumour necrosis factor (TNF) is a pro-inflammatory cytokine contributing to granuloma formation and high levels of TNF have been shown to associate with progressive disease. Mononuclear phagocytes (MNPs) are potent producers of TNF and highly responsive to inflammation. In sarcoidosis, alveolar macrophages have been well studied. However, MNPs also include monocytes/monocyte-derived cells and dendritic cells, which are poorly studied in sarcoidosis, despite their central role in inflammation.ObjectiveTo determine the role of pulmonary monocyte-derived cells and dendritic cells during sarcoidosis.MethodsWe performed in-depth phenotypic, functional and transcriptomic analysis of MNP subsets from blood and bronchoalveolar lavage (BAL) fluid from 108 sarcoidosis patients and 30 healthy controls. We followed the clinical development of patients and assessed how the repertoire and function of MNP subsets at diagnosis correlated with 2-year disease outcome.ResultsMonocytes/monocyte-derived cells were increased in blood and BAL of sarcoidosis patients compared to healthy controls. Interestingly, high frequencies of blood intermediate monocytes at time of diagnosis associated with chronic disease development. RNA sequencing analysis showed highly inflammatory MNPs in BAL of sarcoidosis patients. Furthermore, frequencies of BAL monocytes/monocyte-derived cells producing TNF without exogenous stimulation at time of diagnosis increased in patients that were followed longitudinally. In contrast to alveolar macrophages, the frequency of TNF-producing BAL monocytes/monocyte-derived cells at time of diagnosis was highest in sarcoidosis patients that developed progressive disease.ConclusionOur data show that pulmonary monocytes/monocyte-derived cells are highly inflammatory and can be used as a predictor of disease outcome in sarcoidosis patients.
Highlights
Sarcoidosis is a multisystemic T-cell driven inflammatory disorder of unknown aetiology with broad clinical heterogeneity
All patients were newly diagnosed with pulmonary sarcoidosis as defined by World Association for Sarcoidosis and Other Granulomatous Disorders guidelines [26] based on clinical signs, chest radiography findings, an elevated CD4/CD8 T-cell ratio in bronchoalveolar lavage (BAL) or noncaseating granulomas in tissue biopsies. 20 patients were diagnosed with Löfgren’s syndrome (LS) based on clinical signs
CD14+CD16+monocytes/monocyte-derived cells are increased in blood and BAL of sarcoidosis patients To investigate the frequencies of Mononuclear phagocytes (MNPs) subsets in LS and non-LS sarcoidosis compared to healthy controls we performed multicolour flow cytometry on matched BAL and blood samples
Summary
Sarcoidosis is a multisystemic T-cell driven inflammatory disorder of unknown aetiology with broad clinical heterogeneity. The hallmark of sarcoidosis is formation of granulomas that most commonly affect the lungs. Sarcoidosis patients present with an acute disease onset, referred to as Löfgren’s syndrome (LS) that associates with good prognosis. Two-thirds of patients present with gradual-onset (non-LS) sarcoidosis and these patients are more likely to develop chronic disease [5]. Pulmonary sarcoidosis is an inflammatory disease characterised by granuloma formation and heterogeneous clinical outcome. Tumour necrosis factor (TNF) is a pro-inflammatory cytokine contributing to granuloma formation and high levels of TNF have been shown to associate with progressive disease. MNPs include monocytes/ monocyte-derived cells and dendritic cells, which are poorly studied in sarcoidosis, despite their central role in inflammation
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