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TLR8 influences the production of disease-related cytokines
Systemic sclerosis is an autoimmune disease that primarily causes inflammation of the skin, as well as internal organs such as the lungs and heart. It is considered a rare disease, and little is yet known about its development and progression. In cooperation with the Departments of Rheumatology and Immunology, as well as Dermatology at the Hannover Medical School, a team led by junior research group leader Theresa Graalmann at TWINCORE, Centre for Experimental and Clinical Infection Research, has investigated the role of a specific group of immune cells in people with systemic sclerosis.
They found that certain signalling pathways are active in other cells than previously suspected. The researchers have published their findings in the journal Arthritis & Rheumatology.
Patients with systemic sclerosis suffer from skin changes that are not caused by viruses or bacteria, but by their own immune system. This is why it is referred to as an autoimmune disease. Systemic sclerosis is classified as an orphan disease because the number of people affected is very low. The development of the disease is therefore not yet fully understood. Studies on immune cells from patients have recently shown that the gene for the protein Toll-like receptor 8 (TLR8) is more strongly activated in certain cells than in healthy individuals. TLR8 is a cellular receptor that is normally activated by certain viruses and then triggers a reaction of the immune cells.
The team from Hannover wanted to examine this finding more closely at the level of the actual protein quantities present. To do this, they first isolated plasmacytoid dendritic cells from the skin and blood of ten people with systemic sclerosis. ‘We examined these cells using flow cytometry,’ says Christine Ehlers, a PhD student in the Translational Immunology research group at TWINCORE. ‘This enables us to measure the concentration of receptors and immune messengers, so-called cytokines, in the cells.’ They compared the measured values with those of healthy subjects and also with those of patients with another autoimmune disease, Sjögren's syndrome. However, they could not detect a difference in the concentration of TLR8.
The scientists then stimulated the receptor by adding various agonists. This sets the signalling chain in motion and leads to the production of cytokines in the cell, which in turn can trigger further steps in the immune response. However, in this series of experiments, neither the TLR8 concentrations nor the amount of cytokines produced differed. ‘We saw that TLR8 works in principle, but we were able to show that the receptor plays no role in plasmacytoid dendritic cells in systemic sclerosis,‘ says research group leader Theresa Graalmann.
‘Nevertheless, we did discover one difference,’ adds Ehlers. ‘The monocytes from the scleroderma samples showed increased production of IL-10 after activation of TLR8. We did not observe this in our control group with Sjögren's syndrome.’ IL-10 stands for interleukin-10. This cytokine has an anti-inflammatory but also profibrotic effect, i.e. it promotes the abnormal growth of connective tissue. “IL-10 could contribute to the fibrotic skin changes that are characteristic of systemic sclerosis,” says Graalmann.
The researchers in Theresa Graalmann's team have thus made a significant step forward in elucidating the causes of systemic sclerosis. ‘Unfortunately, however, we cannot yet draw any direct conclusions for treatment because the number of patients is so small,’ Graalmann regrets. ‘However, developing a better molecular understanding of the inflammatory reactions during such a disease is the first step on the road to new and better therapies for the affected patients.’
Dr. Dr. Theresa Graalmann, theresa.graalmann@twincore.de
Tel: +49 (0)511 220027-169
Christine Ehlers, Thea Thiele, Hannah Biermann, Stephan Traidl, Luzia Bruns, Annett Ziegler, Matthias Schefzyk, Lea M. Bartsch, Ulrich Kalinke, Torsten Witte, Theresa Graalmann
Toll-Like Receptor 8 is Expressed in Monocytes in Contrast to Plasmacytoid Dendritic Cells and Mediates Aberrant Interleukin-10 Responses in Patients With Systemic Sclerosis
Arthritis & Rheumatology, 2024
https://doi.org/10.1002/art.42964
https://www.twincore.de/en/infothek-and-press/infothek-news-single/news/new-appr...
http://This press release on twincore.de
Christine Ehlers (left) and Theresa Graalmann in the lab.
©TWINCORE/Grabowski
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