Artikel
Monocytes but not plasmacytoid dendritic cells show aberrant TLR8 signaling in patients with systemic sclerosis (SSc)
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Autoren
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Theresa Graalmann
- Hannover Medical School, Department for Rheumatology and Immunology, Hannover; TWINCORE, Centre for Experimental and Clinical Infection Research, a joint venture between the Helmholtz Centre for Infection Research and the Hannover Medical School, Junior Research Group for Translational Immunology, Hannover; Biomedical Research in End-Stage and Obstructive Lung Disease Hannover (BREATH), German Center for Lung Research (DZL), Hannover
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Christine Ehlers
- TWINCORE, Centre for Experimental and Clinical Infection Research, a joint venture between the Helmholtz Centre for Infection Research and the Hannover Medical School, Junior Research Group for Translational Immunology, Hannover
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Thea Thiele
- Hannover Medical School, Department for Rheumatology and Immunology, Hannover
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Luzia Bruns
- Biomedical Research in End-Stage and Obstructive Lung Disease Hannover (BREATH), German Center for Lung Research (DZL), Hannover
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Annett Ziegler
- TWINCORE, Centre for Experimental and Clinical Infection Research, a joint venture between the Helmholtz Centre for Infection Research and the Hannover Medical School, Experimental Infection Research, Hannover
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Ulrich Kalinke
- TWINCORE, Centre for Experimental and Clinical Infection Research, a joint venture between the Helmholtz Centre for Infection Research and the Hannover Medical School, Experimental Infection Research, Hannover
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Matthias Schefzyk
- Hannover Medical School, Department for Dermatology and Allergy, Hannover
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Torsten Witte
- Hannover Medical School, Department for Rheumatology and Immunology, Hannover
| Veröffentlicht: | 18. September 2024 |
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Gliederung
Text
Introduction: Systemic sclerosis (SSc) is a severe rheumatic disease, leading to inflammation and fibrotic tissue rearrangement of different organs like skin, lung, and heart. Increased type I interferon (IFN-I) signaling in blood and affected tissue was shown to mediate inflammation in SSc. Accordingly, the IFN-I receptor blocking monoclonal antibody anifrolumab is currently tested in a clinical trial in patients suffering from SSc. Recently, aberrant expression of Toll-like receptor 8 (TLR8) transcripts in blood-derived plasmacytoid dendritic cells (pDCs) of patients with SSc was postulated to contribute to IFN-I responses and accordingly to the pathogenesis of SSc [1], [2].
Methods: Peripheral blood mononuclear cells (PBMC) were isolated from patients with SSc, patients with primary Sjögren’s Syndrome (pSS) and healthy controls. Immune cell subsets were identified by flow cytometry and intracellular TLR8 protein expression was specifically analyzed after intracellular labeling. To assess the function of TLR8 in different immune cell subsets, PBMC were stimulated with different synthetic agonists. Following stimulation intracellular cytokine expression was measured by flow cytometry.
Results: Here we report that pDC from patients with SSc do not express TLR8 protein, as similarly detected in pDC from healthy controls. Accordingly, TLR8 stimulation of primary pDC from controls and SSc patients did not induce IFN-I expression. In contrast, the number of monocytes was significantly increased in patients with SSc and these cells showed robust TLR8 expression. Upon TLR8 stimulation monocytes of patients with SSc did not mount IFN-I responses, but showed similar IL-6 and significantly increased levels of IL-10 when compared with monocytes from healthy donors or from patients with primary Sjögren’s syndrome.
Conclusion: Aberrant TLR8 expression is not detected in pDC from patients with SSc and accordingly such cells are not the functional source of increased systemic IFN-I levels in SSc. In contrast, monocytes from patients with SSc show functional TLR8 signaling and upon stimulation with TLR8 agonists these cells mount cytokine responses including increased IL-10.
Disclosures: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.
References
- 1.
- Ah Kioon MD, Tripodo C, Fernandez D, Kirou KA, Spiera RF, Crow MK, Gordon JK, Barrat FJ. Plasmacytoid dendritic cells promote systemic sclerosis with a key role for TLR8. Sci Transl Med. 2018 Jan 10;10(423):eaam8458. DOI: 10.1126/scitranslmed.aam8458
- 2.
- Barrat FJ, Crow MK, Ivashkiv LB. Interferon target-gene expression and epigenomic signatures in health and disease. Nat Immunol. 2019 Dec;20(12):1574-83. DOI: 10.1038/s41590-019-0466-2
