TY - JOUR T1 - Monocytes in sarcoidosis are potent TNF producers and predict disease outcome JF - European Respiratory Journal JO - Eur Respir J DO - 10.1183/13993003.03468-2020 SP - 2003468 AU - Rico Lepzien AU - Sang Liu AU - Paulo Czarnewski AU - Mu Nie AU - Björn Österberg AU - Faezzah Baharom AU - Jamshid Pourazar AU - Gregory Rankin AU - Anders Eklund AU - Matteo Bottai AU - Susanna Kullberg AU - Anders Blomberg AU - Johan Grunewald AU - Anna Smed-Sörensen Y1 - 2021/01/01 UR - http://erj.ersjournals.com/content/early/2021/01/08/13993003.03468-2020.abstract N2 - Background Pulmonary sarcoidosis is an inflammatory disease characterised by granuloma formation and heterogeneous clinical outcome. TNF is a proinflammatory 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 (AMs) have been well studied. However, MNPs also include monocytes/monocyte-derived cells and dendritic cells (DCs) that despite their central role in inflammation are poorly studied in sarcoidosis.Objective To determine the role of pulmonary monocyte-derived cells and DCs during sarcoidosis.Methods We performed in-depth phenotypic, functional and transcriptomic analysis of MNPs 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.Results Monocytes/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. RNAseq 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 AMs, the frequency of TNF producing BAL monocytes/monocyte-derived cells at time of diagnosis was highest in sarcoidosis patients that developed progressive disease.Conclusion Our data show that pulmonary monocytes/monocyte-derived cells are highly inflammatory and can be used as a predictor of disease outcome in sarcoidosis patients.FootnotesThis manuscript has recently been accepted for publication in the European Respiratory Journal. It is published here in its accepted form prior to copyediting and typesetting by our production team. After these production processes are complete and the authors have approved the resulting proofs, the article will move to the latest issue of the ERJ online. Please open or download the PDF to view this article.Conflict of interest: Dr. Funke-Chambour reports grants from roche, grants and personal fees from Boehringer Ingelheim, outside the submitted work;. Dr. Funke-Chambour reports grants from roche, grants and personal fees from Boehringer Ingelheim, outside the submitted work;.Conflict of interest: Dr. Lepzien has nothing to disclose.Conflict of interest: Dr. Liu has nothing to disclose.Conflict of interest: Dr. Czarnewski has nothing to disclose.Conflict of interest: Dr. Nie has nothing to disclose.Conflict of interest: Dr. Österberg has nothing to disclose.Conflict of interest: Dr. Baharom has nothing to disclose.Conflict of interest: Dr. Pourazar has nothing to disclose.Conflict of interest: Dr. Rankin has nothing to disclose.Conflict of interest: Dr. Eklund has nothing to disclose.Conflict of interest: Dr. Bottai has nothing to disclose.Conflict of interest: Dr. Kullberg has nothing to disclose.Conflict of interest: Dr. Blomberg has nothing to disclose.Conflict of interest: Dr. Grunewald has nothing to disclose.Conflict of interest: Dr. Smed-Sorensen reports grants from Swedish Heart-Lung Foundation, grants from Swedish Research Council, grants from Karolinska Institutet, during the conduct of the study. ER -