Timothy Radstake has been awarded an ERC starter grant of € 1.5 million

Radstake Tim

Timothy Radstake (Department of Rheumatology) will use this grant during the next five years to investigate the role of plasmacytoid dendritic (pDCs) cells in systemic sclerosis (SSc). SSc is an autoimmune disease which culminates in excessive extra-cellular matrix deposition (fibrosis) in skin and internal organs. Although the downstream pathways that lead to fibrosis remain obscure, to date much of the research still centralises fibroblasts in its pathology.

Over the past three years several crucial observations made by Radstake's group changed the landscape of our thinking about the ethiopathogenesis of this disease. First, plasmacytoid dendritic cells (pDCs) were found to be extremely frequent in the circulation of SSc patients (1000-fold) in comparison with healthy individuals. In addition, it was found that pDCs from SSc patients are largely dedicated to synthesize CXCL4 which was proven to be directly implicated in fibroblast biology and endothelial cell activation, two events recapitulating SSc.

Finally, research aimed to decipher the underlying cause of these increased pDCs frequently lead to the observation that Runx3, a transcription factor which controls the differentiation of DC subsets, was practically not expressed in pDC of SSc patients. Together, these observations have lead to the "SSc immune postulate" in which the pathogenesis of SSc is explained by a multi-step process in which pDCs play a central role.

The project CIRCUMVENT is designed to provide proof of concept for the role of pDCs in SSc and to open novel avenues for therapeutic targeting of this disease.



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