Sarcoidosis is the name of an inflammatory systemic disease that is characterized by an excessive immune response and accumulations of immune cells in the tissue – so-called granulomas. Such granulomatous diseases pose great challenges for doctors and researchers because the trigger for the underlying immune reaction is unknown. For the first time, scientists at the CeMM – Research Center for Molecular Medicine of the Austrian Academy of Sciences (ÖAW), the Medical University of Vienna and the Ludwig Boltzmann Institute for Rare and Undiagnosed Diseases have now succeeded in characterizing granulomas in the skin in detail. The results provide numerous insights into the composition, structure and signaling pathways of the granuloma, which provide indications for new therapeutic approaches. The study was published in the journal Immunity.
MACROPHAGES, T-CELLS and FIBROBLASTS FORM THE GRANULOMAS
In granulomas we find various building blocks of our immune system that have got mixed up. The cells communicate, but they no longer understand each other. In this way, more and more cells accumulate, which activate each other and lead to inflammation. Health problems arise when granulomas spread throughout the body, develop in organs and cause problems there that can lead to the organ in question failing,” explains project manager Georg Stary, Associate Professor at MedUni Vienna and CeMM Adjunct Principal investigator.
“It becomes a health problem when granulomas spread throughout the body, develop in organs and cause problems there that can lead to organ failure.”
Together with the research group led by Christoph Bock, co-head of the study, CeMM Principal Investigator and MedUni Vienna professor, it was possible to create a detailed picture of the composition, structure and components of granulomas for the first time using single-cell sequencing and methods for spatial analysis of tissue samples.
For the study, the first authors Thomas Krausgruber and Daniele Barreca, scientists in Bock’s research group, together with Anna Redl, analyzed the tissue samples from 12 patients with sarcoid and compared the granulomas with healthy-appearing skin. Using single-cell sequencing, the scientists were able to characterize the details of the granulomas: they mainly consist of macrophages, which actually serve to defend once morest unwanted viruses, bacteria and toxins. There are also specialized T cells. They are surrounded by fibroblasts that give the granuloma its shape.
INHIBITION OF ENZYME “MMP12” REDUCES SWELLING
Inside the macrophages, however, the scientists found an important clue: the protein MMP12, which is particularly important in tissue remodeling, is expressed more strongly than usual in the macrophages in sarcodiosis. “This enzyme seems to play an important role in the formation of granulomas,” explains Thomas Krausgruber. First in-vivo tests on the mouse model have already shown that inhibiting MMP12 reduces swelling. The authors see this as important Starting point for the development of new therapies.
