scholarly journals Distinct immune regulatory receptor profiles linked to altered monocyte subsets in sarcoidosis

2020 ◽  
pp. 00804-2020
Author(s):  
Simon D. Fraser ◽  
Michael G. Crooks ◽  
Paul M. Kaye ◽  
Simon P. Hart
Keyword(s):  
Inflammatory Responses ◽  
Pulmonary Sarcoidosis ◽  
Receptor Expression ◽  
Healthy Controls ◽  
Blood Monocytes ◽  
Monocyte Subsets ◽  
Oral Corticosteroids ◽  
Duration Of Disease ◽  
Classical Monocytes ◽  
Intermediate Monocytes

BackgroundIn sarcoidosis, blood monocytes, circulating precursors of granuloma macrophages, display enhanced inflammatory cytokine production, reduced expression of the regulatory (inhibitory) receptor CD200R, and altered subsets defined by CD14 and CD16. Regulatory receptors serve to dampen monocyte and macrophage inflammatory responses. We investigated the relationship between monocyte subsets and regulatory receptor expression in sarcoidosis.MethodsMulti-parameter flow cytometry was used to perform detailed analyses of cell surface regulatory molecules on freshly isolated blood immune cells from patients with chronic pulmonary sarcoidosis and age-matched healthy controls.ResultsTwenty-five patients with chronic pulmonary sarcoidosis (median duration of disease 22 months) who were not taking oral corticosteroids or other immunomodulators were recruited. Non-classical monocytes were expanded in sarcoidosis and exhibited significantly lower expression of regulatory receptors CD200R, SIRP-α, and CD47 than classical or intermediate monocytes. In sarcoidosis, all three monocyte subsets had significantly reduced CD200R and CD47 expression compared with healthy controls. A dichotomous distribution of CD200R was seen on classical and intermediate monocytes in the sarcoidosis population, with 14/25 (56%) sarcoidosis patients having a CD200R-low phenotype, and 11/25 (44%) CD200R-high. These distinct sarcoidosis monocyte phenotypes remained consistent over time.ConclusionNon-classical monocytes, which are expanded in sarcoidosis, express very low levels of regulatory receptors. Two distinct and persistent phenotypes of CD200R expression in classical and intermediate monocytes could be evaluated as sarcoidosis biomarkers.

scholarly journals Human T Cell Leukemia Virus Type 1 Infection of the Three Monocyte Subsets Contributes to Viral Burden in Humans

2015 ◽  
Vol 90 (5) ◽  
pp. 2195-2207 ◽  
Author(s):  
Maria Fernanda de Castro-Amarante ◽  
Cynthia A. Pise-Masison ◽  
Katherine McKinnon ◽  
Robyn Washington Parks ◽  
Veronica Galli ◽  
...  
Keyword(s):  
T Cells ◽  
Leukemia Virus ◽  
Receptor Expression ◽  
Monocyte Subsets ◽  
Viral Dna ◽  
Cell Leukemia Virus Type ◽  
Human T Cell ◽  
T Cell Leukemia Virus ◽  
Classical Monocytes ◽  
Intermediate Monocytes

ABSTRACTBecause the viral DNA burden correlates with disease development, we investigated the contribution of monocyte subsets (classical, intermediate, and nonclassical monocytes) to the total viral burden in 22 human T cell leukemia virus type 1 (HTLV-1)-infected individuals by assessing their infectivity status, frequency, as well as chemotactic and phagocytic functions. All three monocyte subsets sorted from HTLV-1-infected individuals were positive for viral DNA, and the frequency of classical monocytes was lower in the blood of HTLV-1-infected individuals than in that of uninfected individuals, while the expression levels of the chemokine receptors CCR5, CXCR3, and CX3CR1 in classical monocytes were higher in HTLV-1-infected individuals than uninfected individuals; the percentage of intermediate monocytes and their levels of chemokine receptor expression did not differ between HTLV-1-infected and uninfected individuals. However, the capacity of intermediate monocytes to migrate to CCL5, the ligand for CCR5, was higher, and a higher proportion of nonclassical monocytes expressed CCR1, CXCR3, and CX3CR1. The level of viral DNA in the monocyte subsets correlated with the capacity to migrate to CCL2, CCL5, and CX3CL1 for classical monocytes, with lower levels of phagocytosis for intermediate monocytes, and with the level of viral DNA in CD8+and CD4+T cells for nonclassical monocytes. These data suggest a model whereby HTLV-1 infection augments the number of classical monocytes that migrate to tissues and become infected and the number of infected nonclassical monocytes that transmit virus to CD4+and CD8+T cells. These results, together with prior findings in a macaque model of HTLV-1 infection, support the notion that infection of monocytes by HTLV-1 is likely a requisite for viral persistence in humans.IMPORTANCEMonocytes have been implicated in immune regulation and disease progression in patients with HTLV-1-associated inflammatory diseases. We detected HTLV-1 DNA in all three monocyte subsets and found that infection impacts surface receptor expression, migratory function, and subset frequency. The frequency of nonclassical patrolling monocytes is increased in HTLV-1-infected individuals, and they have increased expression of CCR1, CXCR3, and CX3CR1. The viral DNA level in nonclassical monocytes correlated with the viral DNA level in CD4+and CD8+T cells. Altogether, these data suggest an increased recruitment of classical monocytes to inflammation sites that may result in virus acquisition and, in turn, facilitate virus dissemination and viral persistence. Our findings thus provide new insight into the importance of monocyte infection in viral spread and suggest targeting of monocytes for therapeutic intervention.

scholarly journals Monocytes of Different Subsets in Complexes with Platelets in Patients with Myocardial Infarction

2018 ◽  
Vol 118 (11) ◽  
pp. 1969-1981 ◽  
Author(s):  
Marina Loguinova ◽  
Natalia Pinegina ◽  
Valeria Kogan ◽  
Murad Vagida ◽  
Anush Arakelyan ◽  
...  
Keyword(s):  
Myocardial Infarction ◽  
Annexin V ◽  
Published Data ◽  
Healthy Controls ◽  
New Information ◽  
Platelet Antigen ◽  
Classical Monocytes ◽  
Intermediate Monocytes

AbstractAcute myocardial infarction (AMI) is associated with activation of various cells, including platelets that form monocyte–platelet complexes (MPCs). Here, we analysed MPC in vivo and in vitro and investigated the abilities of different monocyte subclasses to form MPC, the characteristics of the cells involved in MPC formation and MPC changes in AMI. We identified MPC by co-staining for platelet antigen CD41a and monocyte antigens CD14 and CD16. Platelet activation was evaluated from expression of phosphatidylserine as revealed by annexin V. Our results confirm published data and provide new information regarding the patterns of MPC in AMI patients. We found that the patterns of platelet aggregation with monocytes were different in AMI patients and controls: (1) in AMI patients, MPC formed by intermediate monocytes carry more platelets whereas in healthy controls more platelets aggregated with classical monocytes; (2) the numbers of MPC in AMI patients, being already higher than in controls, were further increased if these patients suffered various in-hospital complications; (3) on the basis of the CD41a fluorescence of the antibody-stained MPC, some of the aggregates seem to consist of monocytes and platelet-derived extracellular vesicles (EVs); (4) aggregation of monocytes with platelet EV occurred in in vitro experiments; and (5) these experiments demonstrated that monocytes from AMI patients aggregate with both platelets and platelet EVs more efficiently than do monocytes from controls. MPC in AMI patients may play an important role in this pathology.

scholarly journals A Pilot Study of Circulating Monocyte Subsets in Patients Treated with Stem Cell Transplantation for High-Risk Hematological Malignancies

Medicina ◽  
2020 ◽  
Vol 56 (1) ◽  
pp. 36 ◽  
Author(s):  
Ida Marie Rundgren ◽  
Elisabeth Ersvær ◽  
Aymen Bushra Ahmed ◽  
Anita Ryningen ◽  
Øystein Bruserud
Keyword(s):  
Stem Cell ◽  
High Risk ◽  
Stem Cell Transplantation ◽  
Cell Transplantation ◽  
Peripheral Blood ◽  
Hematological Malignancies ◽  
Peripheral Blood Monocyte ◽  
Healthy Controls ◽  
Monocyte Subsets ◽  
Classical Monocytes

Background and Objectives: Autologous and allogeneic stem cell transplantation is used in the treatment of high-risk hematological malignancies, and monocytes are probably involved in hematological reconstitution as well as posttransplant immunoregulation. The aim of our study was to investigate the levels of circulating monocyte subsets in allotransplant recipients. Materials and Methods: The levels of the classical, intermediate, and nonclassical monocyte subsets were determined by flow cytometry. Sixteen patients and 18 healthy controls were included, and the levels were analyzed during pretransplant remission (n = 13), early posttransplant during cytopenia (n = 9), and early reconstitution (n = 9). Results: Most patients in remission showed a majority of classical monocytes. The patients showed severe early posttransplant monocytopenia, but the total peripheral blood monocyte counts normalized very early on, and before neutrophil and platelet counts. During the first 7–10 days posttransplant (i.e., during cytopenia) a majority of the circulating monocytes showed a nonclassical phenotype, but later (i.e., 12–28 days posttransplant) the majority showed a classical phenotype. However, the variation range of classical monocytes was wider for patients in remission and during regeneration than for healthy controls. Conclusions: The total peripheral blood monocyte levels normalize at the very early stages and before neutrophil reconstitution after stem cell transplantation, and a dominance of classical monocytes is reached within 2–4 weeks posttransplant.

scholarly journals Leukocyte toll-like receptor expression in pathergy positive and negative Behçet’s disease patients

Rheumatology ◽  
2020 ◽  
Vol 59 (12) ◽  
pp. 3971-3979
Author(s):  
Tim B van der Houwen ◽  
Willem A Dik ◽  
Marco Goeijenbier ◽  
Manizhah Hayat ◽  
Nicole M A Nagtzaam ◽  
...  
Keyword(s):  
T Lymphocytes ◽  
Behçet’S Disease ◽  
Behcet’S Disease ◽  
Behçet's Disease ◽  
Receptor Expression ◽  
Healthy Controls ◽  
Toll Like Receptor ◽  
Behcet's Disease ◽  
Tnf Α ◽  
Classical Monocytes

Abstract Objectives To investigate whether the auto-inflammatory nature and the pathergic reaction in Behçet’s disease (BD) are driven by a disturbed toll-like receptor (TLR) response. Methods We compared both TLR expression by flow-cytometry and TLR response by stimulation assay in 18 BD patients (both pathergy positive and pathergy negative) with 15 healthy controls. Results Expression of TLR1 and 2 was significantly elevated in B-lymphocytes of BD patients compared with healthy controls. TLR1, 2 and 4 were significantly more highly expressed in both CD4+ and CD8+ T-lymphocytes of BD patients. Granulocytes of BD patients displayed significantly higher expression of TLR1, 2, 4 and 6. TLR2, 4 and 5 expression was significantly increased on classical monocytes of BD patients. Intermediate monocytes of BD patients showed an increase in expression of TLR2. Furthermore, TLR2 and 5 were significantly more highly expressed in non-classical monocytes of BD patients. In pathergy positive patients, TLR5 was even more highly expressed compared with pathergy negative patients on B- and T-lymphocytes and granulocytes. Furthermore, TLR2 and 5 showed an elevated TNF-α response to stimulation with their cognate ligands. Conclusion Immune cells of BD patients overexpress TLR1, 2, 4, 5 and 6. Furthermore, after stimulation of TLR2 and 5, BD patients demonstrate a more potent TNF-α response. Although this is a small cohort, in the pathergy positive patients, TLR5 expression is even further augmented, suggesting that a microbial (flagellin) or damage (HMGB1) associated signal may trigger the exaggerated immune response that is characteristic for the pathergy phenomenon in BD. In conclusion, these results point to an exaggerated TLR response in the auto-inflammatory nature of BD.

Receptors to interleukin-6 and adhesion molecules on circulating monocyte subsets in acute myocardial infarction

2013 ◽  
Vol 110 (08) ◽  
pp. 340-348 ◽  
Author(s):  
Benjami Wrigley ◽  
Silvia Montoro-Garcia ◽  
Eduard Shantsila ◽  
Luke Tapp ◽  
Gregory Lip
Keyword(s):  
Myocardial Infarction ◽  
Adhesion Molecule ◽  
Interleukin 6 ◽  
Inflammatory Responses ◽  
Stable Coronary Artery Disease ◽  
Annexin V ◽  
Receptor Expression ◽  
Tissue Type ◽  
Intercellular Adhesion Molecule ◽  
Monocyte Subsets

SummaryThe role of individual monocyte subsets in inflammation and recovery post-myocardial infarction (MI) is insufficiently understood. It was the objective of this study to evaluate the dynamics of monocyte expression of receptors to vascular cell adhesion molecule (VCAM-1r), intercellular adhesion molecule (ICAM-1r), and interleukin-6 (IL-6r) following MI and their relation to inflammatory cytokines, fibrinolytic factors and annexin V-binding microparticles. Expression of VCAM-1r, ICAM-1r, IL-6r on CD14++CD16–(Mon1), CD14++CD16+(Mon2), CD14+CD16++(Mon3) monocyte subsets were quantified by flow cytometry in patients with ST-elevation MI (STEMI, n=50), non-STEMI (n=48) and stable coronary artery disease (n=40). In STEMI, parameters were measured on days 1, 3, 7, 30. On admission with STEMI, VCAM-1r expression was reduced on Mon1 (p=0.007), Mon2 (p=0.036), Mon3 (p=0.005), whilst in NSTEMI there was significant up-regulation of expression by Mon2 (p=0.024) and Mon3 (p=0.049). VCAM-1r on Mon1 correlated positively with plasma IL-1β levels (p=0.001). IL-6r was reduced on Mon2 in acute STEMI, with upregulation of the receptor on Mon1 and Mon2 during follow-up. IL-6r density correlated negatively with plasma levels of tissue-type plasminogen activator (p=0.0005 for Mon1, p=0.001 for Mon2 and Mon3), and positively with annexin V-binding microparticles (p=0.03 for Mon1, p=0.005 for Mon2 and p=0.005 for Mon3). There was no change in monocyte ICAM-1r expression. In conclusion, expression of IL-6r and VCAM-1r is reduced on circulating monocyte subsets involved in inflammatory responses in STEMI. This may represent a regulatory feed-back mechanism aiming to re-balance the marked inflammation which is typically present following acute MI or selective homing of monocytes with high receptor expression to damaged myocardium.Note: The review process for this manuscript was fully handled by Christian Weber, Editor in Chief.

scholarly journals Relationship between dynamic changes in subpopulations of blood monocytes and the development of complications in patients with acute myocardial infarction

2020 ◽  
Vol 27 (4) ◽  
pp. 9-17
Author(s):  
T. V. Talayeva ◽  
O. M. Parkhomenko ◽  
I. V. Tretyak ◽  
O. V. Dovhan ◽  
O. V. Shumakov
Keyword(s):  
Myocardial Infarction ◽  
Absolute Number ◽  
Control Group ◽  
Blood Monocytes ◽  
The Absolute ◽  
Anti Inflammatory ◽  
Classical Monocytes ◽  
Intermediate Monocytes ◽  
Patrolling Monocytes

The aim – to determine the extent of different subpopulations of blood monocytes in acute myocardial infarction (AMI) with ST-segment elevation patients on day 1 and 7 and to evaluate the relationship between their content and the dynamics of changes and the risk of complications after AMI.Materials and methods. The composition of individual subpopulations of monocytes in the peripheral venous blood (and general clinical and biochemical blood tests) was evaluated in 50 pts with STEMI (who were admitted within 6 hours after the onset of the disease) at admission (before primary PCI) and on day 7. All patients received standard recommended therapy. Dynamic heart echocardiography was also performed on the 1st and 7th day. All patients were divided into 2 groups depending on the dynamical increase (1 group – 21 pts) or decrease (2 group – 29 pts) of classical monocytes (CD14hiCD16–) subpopulation during 7 days of follow-up. The control group included 15 healthy subjects with no signs of coronary heart disease and 23 pts with chronic coronary heart disease without AMI.Results and discussion. In subgroup 1, the percentage of the «classical» fraction of monocytes during the observation increased to 89.0±1.2 %, which was 4.2 % more than on the 1st day and 12.5 % more than in the control group (р<0.05), while the absolute amount of classic monocytes on day 7 increased by 48 % compared to initial value (р<0.01). The percentage of «intermediate» (CD14hiCD16+) blood monocytes in patients of this subgroup on the 1st day of hospitalization was 70 % higher than in the control group, and 42 % higher than in the 2nd subgroup of patients (р<0,001), however, on the 7th day it decreased by 30 % compared to baseline, although it remained by 8 % more than in the control group (the absolute number of «intermediate» monocytes did not change). The activation index (IA) of the «intermediate» monocytes on the first day did not differ between subgroups and was 40 % higher than in the control group (р<0.001). However, in the dynamics of observation, in patients of subgroup 1, this figure did not change, while in subgroup 2 IA decreased by 60 % (р<0.001). Despite the fact that the absolute number of anti-inflammatory («patrolling») (CD14+lowCD16++) monocytes did not change until the 7th day of observation (and their percentage decreased slightly), their IA was significantly lower than in the control group (95 %) and in patients of subgroup 2 (92 %, р<0,001). In patients of subgroup 2, the decrease of the percentage of «classic» monocytes was –7.7 % (from 90.4±0.8 to 83.4±1.2 %). Despite the fact that the number and percentage of intermediate monocytes increased in dynamics, their IA decreased almost 2 times, which may indicate a decrease in the pro-inflammatory ability these monocytes. The percentage and number of «patrolling» monocytes increased in dynamics by 37.4 % (р<0.0001) and by 268.3 % (р<0.01), respectively. IA of patrolling monocytes was almost 12 and 7 times higher than in patients of subgroup 1 on the 1st and 7th day of observation, respectively, which may indicate a significant activation of anti-inflammatory activity of patrolling monocytes. Intracardiac thrombosis was 3.3 times more common in patients of subgroup 1, in this subgroup was also more often noted (compared to the subgroup 2): dilatation of the left ventricle (almost 8 times), reduction of left ventricular ejection fraction (4 times), and pathological post-infarction remodeling of the left ventricle (almost 7 times).Conclusions. The results of the study indicate the important role of different subpopulations of blood monocytes in the processes of myocardial damage and recovery (in particular, the pro-inflammatory role of increasing the number of classical monocytes and increasing the activity of intermediate monocytes, as well as the anti-inflammatory role of increasing the number, percentage and activity of patrolling monocytes) in patients with AMI and can be the basis for developing new approaches to the diagnosis and prevention of complications of this disease.

The dysregulation of monocyte subpopulations in individuals at risk of developing rheumatoid arthritis

Rheumatology ◽  
2020 ◽  
Author(s):  
Klára Prajzlerová ◽  
Olga Kryštůfková ◽  
Martin Komarc ◽  
Heřman Mann ◽  
Hana Hulejová ◽  
...  
Keyword(s):  
At Risk ◽  
Peripheral Blood Monocyte ◽  
Lower Percentage ◽  
Healthy Controls ◽  
Monocyte Subsets ◽  
Citrullinated Proteins ◽  
Monocyte Subpopulations ◽  
The Difference ◽  
Definition Of ◽  
Classical Monocytes

Abstract Objectives Individuals carrying antibodies against citrullinated proteins (ACPA) are at high risk of developing RA. EULAR provided a clinical definition of individuals with arthralgia suspicious for progression to RA (clinically suspect arthralgia, CSA). The alteration of monocyte subpopulations in patients with established RA has been previously described. We analysed peripheral blood monocyte subpopulations in individuals with arthralgia at risk of RA. Methods We included 70 at-risk individuals, defined as having arthralgia without arthritis and being either ACPA+ or meeting the clinical CSA definition, 23 patients with early RA (ERA) and 19 healthy controls (HCs). Monocytes classified as classical (CD14++CD16−), intermediate (CD14++CD16+/++) and nonclassical (CD14−/+CD16++) were analysed by flow cytometry. Results Of the 70 at-risk individuals, 46 were ACPA+ and 45 met the CSA definition. The at-risk individuals and, especially, ERA patients had a lower percentage of classical monocytes and a higher percentage of nonclassical monocytes than the HCs. ACPA positivity had no effect on the difference in the distribution of the monocyte subsets between at-risk individuals and ERA patients, but a difference was determined in those reaching the ERA phase. However, when compared with HCs, the shift of monocyte subsets was more significant in ACPA+ than in ACPA− individuals with arthralgia. This trend was observed in individuals who did not meet the CSA definition. This finding was, however, determined by a selection bias, as these individuals were solely ACPA+. Conclusion The shift from classical to nonclassical monocyte subpopulations was observed already in individuals at risk of developing RA.

scholarly journals Neutrophil extracellular traps and monocyte subsets at the culprit lesion site of myocardial infarction patients

2019 ◽  
Vol 9 (1) ◽  
Author(s):  
Andreas Mangold ◽  
Thomas M. Hofbauer ◽  
Anna S. Ondracek ◽  
Tyler Artner ◽  
Thomas Scherz ◽  
...  
Keyword(s):  
Myocardial Infarction ◽  
Infarct Size ◽  
Neutrophil Extracellular Traps ◽  
Lesion Site ◽  
Monocyte Subsets ◽  
Culprit Lesion ◽  
Extracellular Traps ◽  
Classical Monocytes ◽  
Intermediate Monocytes ◽  
Cx3cr1 Expression

Abstract Neutrophils release their chromatin into the extracellular space upon activation. These web-like structures are called neutrophil extracellular traps (NETs) and have potent prothrombotic and proinflammatory properties. In ST-elevation myocardial infarction (STEMI), NETs correlate with increased infarct size. The interplay of neutrophils and monocytes impacts cardiac remodeling. Monocyte subsets are classified as classical, intermediate and non-classical monocytes. In the present study, in vitro stimulation with NETs led to an increase of intermediate monocytes and reduced expression of CX3CR1 in all subsets. Intermediate monocytes have been associated with poor outcome, while non-classical CX3CR1-positive monocytes could have reparative function after STEMI. We characterized monocyte subsets and NET markers at the culprit lesion site of STEMI patients (n = 91). NET surrogate markers were increased and correlated with larger infarct size and with fewer non-classical monocytes. Intermediate and especially non-classical monocytes were increased at the culprit site compared to the femoral site. Low CX3CR1 expression of monocytes correlated with high NET markers and increased infarct size. In this translational system, causality cannot be proven. However, our data suggest that NETs interfere with monocytic differentiation and receptor expression, presumably promoting a subset shift at the culprit lesion site. Reduced monocyte CX3CR1 expression may compromise myocardial salvage.

scholarly journals The fate and lifespan of human monocyte subsets in steady state and systemic inflammation

2017 ◽  
Vol 214 (7) ◽  
pp. 1913-1923 ◽  
Author(s):  
Amit A. Patel ◽  
Yan Zhang ◽  
James N. Fullerton ◽  
Lies Boelen ◽  
Anthony Rongvaux ◽  
...  
Keyword(s):  
Steady State ◽  
Inflammatory Responses ◽  
Dynamic Equilibrium ◽  
Human Monocyte ◽  
Monocyte Subsets ◽  
Deuterium Labeling ◽  
Developmental Relationship ◽  
Endotoxemia Model ◽  
Classical Monocytes

In humans, the monocyte pool comprises three subsets (classical, intermediate, and nonclassical) that circulate in dynamic equilibrium. The kinetics underlying their generation, differentiation, and disappearance are critical to understanding both steady-state homeostasis and inflammatory responses. Here, using human in vivo deuterium labeling, we demonstrate that classical monocytes emerge first from marrow, after a postmitotic interval of 1.6 d, and circulate for a day. Subsequent labeling of intermediate and nonclassical monocytes is consistent with a model of sequential transition. Intermediate and nonclassical monocytes have longer circulating lifespans (∼4 and ∼7 d, respectively). In a human experimental endotoxemia model, a transient but profound monocytopenia was observed; restoration of circulating monocytes was achieved by the early release of classical monocytes from bone marrow. The sequence of repopulation recapitulated the order of maturation in healthy homeostasis. This developmental relationship between monocyte subsets was verified by fate mapping grafted human classical monocytes into humanized mice, which were able to differentiate sequentially into intermediate and nonclassical cells.

scholarly journals Monocytes in sarcoidosis are potent TNF producers and predict disease outcome

2021 ◽  
pp. 2003468
Author(s):  
Rico Lepzien ◽  
Sang Liu ◽  
Paulo Czarnewski ◽  
Mu Nie ◽  
Björn Österberg ◽  
...  
Keyword(s):  
Progressive Disease ◽  
Pulmonary Sarcoidosis ◽  
Mononuclear Phagocytes ◽  
Granuloma Formation ◽  
Disease Outcome ◽  
Healthy Controls ◽  
High Frequencies ◽  
And Function ◽  
Intermediate Monocytes

BackgroundPulmonary 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.ObjectiveTo determine the role of pulmonary monocyte-derived cells and DCs during sarcoidosis.MethodsWe 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.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. 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.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.

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