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Jiemy, W. F., Zhang, A., Abdulahad, W. H., Reitsema, R., van Sleen, Y., Sandovici, M., . . . van der Geest, K. S. M. (2025). GM-CSF drives IL-6 production by macrophages in polymyalgia rheumatica. Annals of the Rheumatic Diseases
Open this publication in new window or tab >>GM-CSF drives IL-6 production by macrophages in polymyalgia rheumatica
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2025 (English)In: Annals of the Rheumatic Diseases, ISSN 0003-4967, E-ISSN 1468-2060Article in journal (Refereed) Epub ahead of print
Abstract [en]

OBJECTIVES: Insight into the immunopathology of polymyalgia rheumatica (PMR) is scarce and mainly derived from peripheral blood studies. The limited data available point towards macrophages as potential key players in PMR. This study aimed to identify the factors driving proinflammatory macrophage development and their functions in the immunopathology of PMR.

METHODS: Monocyte phenotypes were investigated by flow cytometry in peripheral blood (PMR, n = 22; healthy controls, n = 20) and paired subacromial-subdeltoid (SASD) bursal fluid (PMR, n = 9). Macrophages in SASD bursa were characterised by immunohistochemistry and immunofluorescence (PMR, n = 12; controls undergoing shoulder replacement surgery, n = 10). The functions of cytokines expressed in PMR-affected tissue were examined using macrophage differentiation cultures (PMR, n = 7; healthy controls, n = 7).

RESULTS: Monocytes (CD14highCD16- and CD14highCD16+) were increased in blood of PMR patients and activated in bursal fluid. Macrophages dominated immune infiltrates in PMR-affected tissue, expressing various proinflammatory cytokines. While interleukin (IL)-6 and interferon-gamma (IFN-γ) expression was abundant in both PMR and control tissue, granulocyte-macrophage colony-stimulating factor (GM-CSF) and macrophage colony-stimulating factor (M-CSF) were significantly increased in PMR tissue. Macrophages in PMR-affected tissue showed an elevated CD206/folate receptor β ratio, reflecting a GM-CSF skewed signature. A combination of GM-CSF/M-CSF/IFN-γ significantly boosted IL-6 production in vitro, while limited IL-6 production was observed without GM-CSF.

CONCLUSIONS: The monocyte compartment is expanded and activated in PMR. Macrophages in PMR-affected tissue produce abundant proinflammatory cytokines such as IL-6. A network of locally expressed cytokines, including GM-CSF, M-CSF, and IFN-γ, may drive the proinflammatory functions of these macrophages. Overall, macrophages may constitute key therapeutic targets for PMR.

Place, publisher, year, edition, pages
Highwire Press, 2025
National Category
Immunology in the medical area Cell and Molecular Biology
Identifiers
urn:nbn:se:oru:diva-119175 (URN)10.1016/j.ard.2025.01.004 (DOI)39915203 (PubMedID)
Note

Funding Agencies:

The study was supported by a research grant from FOREUM Foundation for Research in Rheumatology (Career Research Grant; KSMvdG). The study was also funded by the Dutch Society for Rheumatology (Rheumatology Grant; KSMvdG), the University of Groningen (AZ), the State Scholarship Fund China (AZ), and the Mandema Stipend (KSMvdG).

Available from: 2025-02-07 Created: 2025-02-07 Last updated: 2025-02-07Bibliographically approved
Reitsema, R. D., Kumawat, A. K., Hesselink, B.-C., van Baarle, D. & van Sleen, Y. (2024). Effects of ageing and frailty on circulating monocyte and dendritic cell subsets. npj aging, 10(1), Article ID 17.
Open this publication in new window or tab >>Effects of ageing and frailty on circulating monocyte and dendritic cell subsets
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2024 (English)In: npj aging, E-ISSN 2731-6068, Vol. 10, no 1, article id 17Article in journal (Refereed) Published
Abstract [en]

Ageing is associated with dysregulated immune responses, resulting in impaired resilience against infections and low-grade inflammation known as inflammageing. Frailty is a measurable condition in older adults characterized by decreased health and physical impairment. Dendritic cells (DCs) and monocytes play a crucial role in initiating and steering immune responses. To assess whether their frequencies and phenotypes in the blood are affected by ageing or frailty, we performed a flow cytometry study on monocyte and DC subsets in an immune ageing cohort. We included (n = 15 in each group) healthy young controls (HYC, median age 29 years), healthy older controls (HOC, 73 years) and Frail older controls (76 years). Monocyte subsets (classical, intermediate, non-classical) were identified by CD14 and CD16 expression, and DC subsets (conventional (c)DC1, cDC2, plasmacytoid (p)DC) by CD11c, CD1c, CD141 and CD303 expression. All subsets were checked for TLR2, TLR4, HLA-DR, CD86, PDL1, CCR7 and CD40 expression. We observed a lower proportion of pDCs in HOC compared to HYC. Additionally, we found higher expression of activation markers on classical and intermediate monocytes and on cDC2 in HOC compared to HYC. Frail participants had a higher expression of CD40 on classical and non-classical monocytes compared to the HOC group. We document a substantial effect of ageing on monocytes and DCs. Reduced pDCs in older people may underlie their impaired ability to counter viral infections, whereas enhanced expression of activation markers could indicate a state of inflammageing. Future studies could elucidate the functional consequences of CD40 upregulation with frailty.

Place, publisher, year, edition, pages
Nature Publishing Group, 2024
National Category
Immunology in the medical area
Identifiers
urn:nbn:se:oru:diva-112127 (URN)10.1038/s41514-024-00144-6 (DOI)001178127600001 ()38438383 (PubMedID)2-s2.0-85186629789 (Scopus ID)
Funder
EU, Horizon 2020
Note

This research has been performed in the context of the VITAL consortium. The VITAL project has received funding from the Innovative Medicines Initiative 2 Joint Undertaking (JU) under grant agreement No. 806776 and the Dutch Ministry of Health, Welfare and Sport. The JU receives support from the European Union's Horizon 2020 research and innovation program and EFPIA-members.

Available from: 2024-03-06 Created: 2024-03-06 Last updated: 2024-03-20Bibliographically approved
Reitsema, R. D., Hesselink, B.-C., Abdulahad, W. H., van der Geest, K. S. M., Brouwer, E., Heeringa, P. & van Sleen, Y. (2023). Aberrant phenotype of circulating antigen presenting cells in giant cell arteritis and polymyalgia rheumatica. Frontiers in Immunology, 14, Article ID 1201575.
Open this publication in new window or tab >>Aberrant phenotype of circulating antigen presenting cells in giant cell arteritis and polymyalgia rheumatica
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2023 (English)In: Frontiers in Immunology, E-ISSN 1664-3224, Vol. 14, article id 1201575Article in journal (Refereed) Published
Abstract [en]

BACKGROUND: Giant Cell Arteritis (GCA) and Polymyalgia Rheumatica (PMR) are overlapping inflammatory diseases. Antigen-presenting cells (APCs), including monocytes and dendritic cells (DCs), are main contributors to the immunopathology of GCA and PMR. However, little is known about APC phenotypes in the peripheral blood at the time of GCA/PMR diagnosis.

METHODS: APCs among peripheral blood mononuclear cells (PBMCs) of treatment-naive GCA and PMR patients were compared to those in age- and sex-matched healthy controls (HCs) using flow cytometry (n=15 in each group). We identified three monocyte subsets, and three DC subsets: plasmacytoid DCs (pDCs), CD141+ conventional DCs (cDC1) and CD1c+ conventional DCs (cDC2). Each of these subsets was analyzed for expression of pattern recognition receptors (TLR2, TLR4), immune checkpoints (CD86, PDL1, CD40) and activation markers (HLA-DR, CD11c).

RESULTS: t-SNE plots revealed a differential clustering of APCs between GCA/PMR and HCs. Further analyses showed shifts in monocyte subsets and a lower proportion of the small population of cDC1 cells in GCA/PMR, whereas cDC2 proportions correlated negatively with CRP (r=-0.52). Classical monocytes of GCA/PMR patients show reduced expression of TLR2, HLA-DR, CD11c, which was in contrast to non-classical monocytes that showed higher marker expression. Additionally, single cell RNA sequencing in GCA patients identified a number of differentially expressed genes related to inflammation and metabolism in APCs.

CONCLUSION: Circulating non-classical monocytes display an activated phenotype in GCA/PMR patients at diagnosis, whereas classical monocytes show reduced expression of activation markers. Whether these findings reflect APC migration patterns or the effects of long-term inflammation remains to be investigated.

Place, publisher, year, edition, pages
Frontiers Media S.A., 2023
Keywords
Dendritic cells, giant cell arteritis, monocytes, polymyalgia rheumatica, vasculitis
National Category
Rheumatology and Autoimmunity Immunology
Identifiers
urn:nbn:se:oru:diva-107819 (URN)10.3389/fimmu.2023.1201575 (DOI)001048865800001 ()37600779 (PubMedID)2-s2.0-85168293371 (Scopus ID)
Available from: 2023-08-24 Created: 2023-08-24 Last updated: 2024-01-17Bibliographically approved
Reitsema, R., Hesselink, B. C., Van der Geest, K., Abdulahad, W., Boots, A., Brouwer, E., . . . Van Sleen, Y. (2023). ABERRANT PHENOTYPE OF CIRCULATING ANTIGEN PRESENTING CELLS IN GIANT CELL ARTERITIS AND POLYMYLAGIA RHEUMATICA. Paper presented at European Congress of Rheumatology (EULAR 2023), Milan, Italy, May 31 - June 3, 2023. Annals of the Rheumatic Diseases, 82(Suppl. 1), 1071-1071, Article ID POS1434.
Open this publication in new window or tab >>ABERRANT PHENOTYPE OF CIRCULATING ANTIGEN PRESENTING CELLS IN GIANT CELL ARTERITIS AND POLYMYLAGIA RHEUMATICA
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2023 (English)In: Annals of the Rheumatic Diseases, ISSN 0003-4967, E-ISSN 1468-2060, Vol. 82, no Suppl. 1, p. 1071-1071, article id POS1434Article in journal, Meeting abstract (Other academic) Published
Abstract [en]

Background: Giant Cell Arteritis (GCA) and Polymyalgia Rheumatica (PMR) are overlapping diseases occurring exclusively in people older than 50 years. Antigen-presenting cells (APCs), including monocytes and dendritic cells (DCs), are main contributors to the immunopathology of GCA and PMR. In GCA tissues, DCs may be prone to activation, leading to chemokine production and recruitment of CD4+ T-cells and monocytes to the arterial wall. However, little is known about APC phenotypes in the peripheral blood at the time of GCA/PMR diagnosis.

Objectives: We aimed to investigate the phenotype of the circulating monocytes and DCs in GCA and PMR patients.

Methods: APCs among peripheral blood mononuclear cells (PBMCs) of treatment-naive GCA and PMR patients were compared to those in age- and sex-matched healthy controls (HCs) using flow cytometry (n=15 in each group). Using a 13-colour panel, we identified three monocyte subsets: classical (CD14+CD16-), intermediate (CD14+CD16+), and non-classical (CD14lowCD16+) monocytes. DC subsets were subdivided in CD303+CD11c- plasmacytoid DCs (pDCs), CD11c+CD141+ conventional DCs (cDC1) and CD11c+CD1c+ conventional DCs (cDC2). Each of these subsets was analysed for expression of pattern recognition receptors (Toll-like receptor 4 (TLR4), TLR2) and activation markers (CD86, Programmed Death- Ligand 1 (PD-L1), CD40, HLA-DR, CD11c) by assessing the mean-fluorescence intensity of these markers. Data were analysed by conventional gating strategies and by unsupervised tSNE.

Results: GCA and PMR patients displayed a monocytosis, which was due to increases in classical and intermediate monocyte counts, whereas the proportion of non-classical monocytes was reduced. Intermediate monocytes of GCA patients had significantly higher TLR2 expression, a similar trend was observed in non-classical monocytes of GCA and PMR patients. A divergent pattern was observed in the expression of activation markers on classical versus non-classical monocytes: classical monocytes of GCA/PMR patients appeared to be less activated, whereas non-classical monocytes showed an increased marker expression compared to HCs (Figure 1). Even though no differences were observed in DC counts in the peripheral blood, cDC2 counts correlated negatively with CRP levels (r=-0.60 for GCA, r=-0.55 for PMR).

Conclusion: Circulating non-classical monocytes, but not DCs, display an activated phenotype in GCA and PMR patients at diagnosis. These cells are thought to be pro-inflammatory, representing the end stage of monocyte maturation in the blood. In contrast, classical monocytes show reduced expression of activation markers in GCA and PMR patients, potentially signalling either an immature or exhausted phenotype. Shown is the mean fluorescence intensity (MFI) of CD11c on the surface of monocyte subsets and CD1c+ conventional dendritic cells (cDC2). Data are shown for patients with giant cell arteritis (GCA) or polymyalgia rheumatica (PMR) and age-matched healthy controls (HCs), n=15 for each group. Statistics by Mann Whitney U. CD11c expression data for pDCs (no CD11c expression) and cDC1 (too small population) are not shown.

Place, publisher, year, edition, pages
HighWire Press, 2023
Keywords
Innate immunity, Vasculitis
National Category
Rheumatology and Autoimmunity
Identifiers
urn:nbn:se:oru:diva-111553 (URN)10.1136/annrheumdis-2023-eular.3189 (DOI)001107398703335 ()
Conference
European Congress of Rheumatology (EULAR 2023), Milan, Italy, May 31 - June 3, 2023
Available from: 2024-02-15 Created: 2024-02-15 Last updated: 2024-02-15Bibliographically approved
van Nieuwland, M., Esen, I., Reitsema, R. D., Abdulahad, W. H., van Sleen, Y., Jiemy, W. F., . . . van Bon, L. (2023). Evidence for increased interferon type I activity in CD8+ T cells in giant cell arteritis patients. Frontiers in Immunology, 14, Article ID 1197293.
Open this publication in new window or tab >>Evidence for increased interferon type I activity in CD8+ T cells in giant cell arteritis patients
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2023 (English)In: Frontiers in Immunology, E-ISSN 1664-3224, Vol. 14, article id 1197293Article in journal (Refereed) Published
Abstract [en]

INTRODUCTION: Giant cell arteritis (GCA) is a vasculitis of the medium- and large-sized arteries. Interferon type I (IFN-I) is increasingly recognized as a key player in autoimmune diseases and might be involved in GCA pathogenesis, however evidence is limited. IFN-I activates Janus kinase/signal transducers and activators of transcription (JAK-STAT) pathways, leading to increased expression of interferon stimulated genes. In this study, IFN-I activity in GCA is explored, focusing on CD8+ T cells.

METHODS: Expression of phospho-STAT (pSTAT) 1, 3 and 5 was investigated in IFN-α-stimulated peripheral mononuclear cells (PBMCs) gated separately for CD8+ T cells of patients with GCA (n=18), healthy controls (HC, n=15) and infection controls (n=11) by Phosphoflow method combined with fluorescent cell barcoding technique. Furthermore, IFN-I induced myxovirus-resistance protein A (MxA) and CD8+ T cell expression was investigated by immunohistochemistry in temporal artery biopsies (TAB) of GCA patients (n=20) and mimics (n=20), and in aorta tissue of GCA (n=8) and atherosclerosis patients (n=14).

RESULTS: pSTAT1 expression was increased in IFN-α stimulated CD8+ T cells from GCA patients, whereas no difference was observed in pSTAT3 and pSTAT5 expression. MxA was present in TABs of 13/20 GCA patients compared to 2/20 mimics and in 8/8 GCA+ compared to 13/14 GCA- aorta tissues. MxA location partially co-localized with CD8+T cells.

CONCLUSIONS: Our results provide evidence for increased IFN-I activity in CD8+ T cells of GCA patients, both systemically and locally. These findings warrant further investigation regarding IFN-I induced biomarkers and IFN-I related novel therapeutic options in GCA.

Place, publisher, year, edition, pages
Frontiers Media S.A., 2023
Keywords
T cell, adaptive immunity, giant cell arteritis, innate immunity, interferon, large vessel vasculitis, vasculitis
National Category
Rheumatology and Autoimmunity
Identifiers
urn:nbn:se:oru:diva-106879 (URN)10.3389/fimmu.2023.1197293 (DOI)001019023900001 ()37398666 (PubMedID)2-s2.0-85164210977 (Scopus ID)
Available from: 2023-07-04 Created: 2023-07-04 Last updated: 2024-01-17Bibliographically approved
Kurt, S., Pirronello, F., Reitsema, R., Demirel, I., Rangel, I., Sirsjö, A., . . . Kumawat, A. (2023). Increased proportion of circulating neutrophils with impaired phagocytosis capacity in patients with peripheral arterial disease. Paper presented at 91st Annual Meeting of the European-Atherosclerosis-Society (EAS 2023), Mannheim, Germany, May 21-24, 2023. Atherosclerosis, 379(Suppl. 1), S22-S22, Article ID P068.
Open this publication in new window or tab >>Increased proportion of circulating neutrophils with impaired phagocytosis capacity in patients with peripheral arterial disease
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2023 (English)In: Atherosclerosis, ISSN 0021-9150, E-ISSN 1879-1484, Vol. 379, no Suppl. 1, p. S22-S22, article id P068Article in journal, Meeting abstract (Other academic) Published
Abstract [en]

Background and Aims: Peripheral arterial disease (PAD) is a clinical manifestation of atherosclerosis, affecting arteries in the leg. Based on their symptoms and severity, PAD patients are characterized into three sub-groups: asymptomatic, intermittent claudication (IC) and critical limb ischemia (CLI). Despite its high prevalence, PAD remains under diagnosed and the role of immune cells in PAD pathophysiology remains poorly understood. In this study, we characterized the innate immune responses in PAD patients compared to healthy controls.

Methods: Blood samples were collected from 14 patients with PAD (IC) and 30 healthy controls, to assess the phenotype of monocytes and neutrophils by using 10-colour flow cytometry. Phagocytosis assay was performed with labelled E.coli particles. Mann-Whitney U non-parametrical test was used for statistical comparison between PAD patients and healthy controls.

Results: A significant higher proportion of leukocytes (p<0.05) and neutrophils (p<0.01) was observed in PAD patients compared to healthy controls, whereas monocyte subsets showed no significant differences. Interestingly, neutrophils showed a significantly impaired phagocytosis capability (p<0.05) and reduced expression of myeloperoxidase (MPO) (p<0.05) in PAD patients compared to healthy controls.

Conclusions: Taken together these results, suggest that PAD patients have an increased proportion of neutrophils in circulation, with impaired phagocytosis capability, compared to healthy controls.

Place, publisher, year, edition, pages
Elsevier, 2023
National Category
Cardiology and Cardiovascular Disease
Identifiers
urn:nbn:se:oru:diva-109555 (URN)001060595800354 ()
Conference
91st Annual Meeting of the European-Atherosclerosis-Society (EAS 2023), Mannheim, Germany, May 21-24, 2023
Available from: 2023-11-06 Created: 2023-11-06 Last updated: 2025-02-10Bibliographically approved
Pirronello, F., Kurt, S., Reitsema, R., Rangel, I., Dreifaldt, M., Sirsjö, A. & Kumawat, A. (2023). Phenotypic and functional characterization of T cell immune responses in peripheral arterial disease. Paper presented at 91st Annual Meeting of the European-Atherosclerosis-Society (EAS 2023), Mannheim, Germany, May 21-24, 2023. Atherosclerosis, 379(Suppl. 1), S25-S25, Article ID P076.
Open this publication in new window or tab >>Phenotypic and functional characterization of T cell immune responses in peripheral arterial disease
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2023 (English)In: Atherosclerosis, ISSN 0021-9150, E-ISSN 1879-1484, Vol. 379, no Suppl. 1, p. S25-S25, article id P076Article in journal, Meeting abstract (Other academic) Published
Abstract [en]

Background and Aims: Peripheral arterial disease (PAD) is a common manifestation of atherosclerosis, affecting the lower limbs. T cells are among the principal contributors to the development of atherosclerotic plaques. However, T cell immune responses in PAD pathophysiology are poorly understood and a detailed phenotypic and functional characterization of T cell immune responses in PAD is needed.

Methods: Blood samples were collected from PAD patients with claudicatio intermittens (n=14) and healthy controls (HCs, n=30). We assessed the phenotype of active, effector and memory T cell subsets by evaluating the expression of specific surface and intracellular markers analysed by 10-colour flow cytometry. Functional responses were evaluated by performing T cell receptor (TCR) stimulation of PBMCs in a 3D cell culture system to assess cytokine production by ELISA. Statistical analyses were performed using the Mann-Whitney U test.

Results: No differences were observed between PAD and HCs in terms of active, effector and memory T cell phenotypes and in the frequency of cells expressing CCR6 and CXCR3 (markers associated with T cells producing IL-17 and IFN-γ). However, lower frequencies of IFN-γ+ cells among CD8+ (P=0.04), and CD4+CD8+ cells (P=0.03) were observed in PAD compared to HCs. TNF-α production in PAD-derived PBMCs, via TCR stimulation was increased at both 48- (P=0.004) and 72-hour time points (P=0.003). No differences were observed in IL-1β, IFN-γ and IL-17 secretion.

Conclusions: Taken together these results suggest that increased TNF-α secretion by PBMCs in response to TCR activation might contribute to the pro-inflammatory environment in PAD pathogenesis.

Place, publisher, year, edition, pages
Elsevier, 2023
National Category
Cardiology and Cardiovascular Disease
Identifiers
urn:nbn:se:oru:diva-109561 (URN)001060595800362 ()
Conference
91st Annual Meeting of the European-Atherosclerosis-Society (EAS 2023), Mannheim, Germany, May 21-24, 2023
Available from: 2023-11-06 Created: 2023-11-06 Last updated: 2025-02-10Bibliographically approved
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ORCID iD: ORCID iD iconorcid.org/0000-0002-4250-0930

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