S100 induced regulation of the immune system in auto-inflammatory diseases

• Applicant: Dr. Philipp Berger
• Subject Area: Rheumatology ; Pediatric and Adolescent Medicine
• Term: from 2021 to 2023
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 460054790

We aim to identify pathophysiological signaling pathways in sterile auto-inflammatory diseases. First of all, we focus on S100-mediated reprogramming of phagocytes in the genetically defined auto-inflammatory syndromes Familial Mediterranean fever (FMF) and PAPA-syndrome, which are characterized by excessive expression of the S100 alarmins.In a secondary step, we attempt to transfer relevant findings from these rare diseases to polygenic systemic-onset juvenile idiopathic arthritis (sJIA) and other more common clinical pictures.The following four milestones will be worked on mainly using murine ER-HoxB8 cells (myeloid progenitor cells) with a confirmation of relevant findings in human leukocytes:1) Do murine monocytes with pyrine or PSTPIP1 defects show an altered inflammatory reaction, development of tolerance or reprogramming?2) Which signaling pathways do S100 alarmins use to influence these processes and which molecular mechanisms are needed to release S100 alarmins in these models?3) What relevance does the S100-induced reprogramming have in the FMF mouse model in vivo?4) Proof of the identified reprogramming mechanisms in the expression profiles of patients with autoinflammatory diseases such as sJIA, FMF and SIRS.Answering these questions will bring further insight into the pathophysiological mechanisms of inflammatory disease in general and specifically for the chosen diseases. Furthermore we aim to identify key mechanisms as targets for a medical approach in curing these diseases.

• DFG Programme: WBP Position