The goal of this project is to improve the diagnosis and management of systemic autoinflammatory diseases (SAIDs), which are rare disorders characterized by periodic fever and sterile systemic inflammation that often mimics infectious diseases. If left untreated, SAIDs can lead to severe complications, such as renal failure, due to chronic inflammation. Diagnosis remains challenging due to the absence of specific diagnostic criteria. While germline and somatic variants have been identified in some patients, the molecular cause remains unknown in approximately 70% of cases, which delays the implementation of targeted treatments.
These diseases result from dysregulated innate immune pathways, notably inflammasome and NF-κB signaling activation. Inflammasomes detect danger signals via sensors such as pyrin, NLRP3, and NLRC4, triggering ASC (apoptosis-associated speck-like protein containing a CARD) assembly, which in turn activates caspase-1, leading to IL-1β and IL-18 secretion and pyroptotic cell death.
To overcome current diagnostic and mechanistic limitations, this project will combine single-cell (sc) analyses of patient-derived blood cells with comprehensive molecular and functional investigations to elucidate disease mechanisms at cellular resolution. This integrative strategy will clarify how genetic variants modulate immune pathways and trigger inflammation.
The project aims to identify novel pathogenic mechanisms, define molecular and functional biomarkers, and develop diagnostic assays that enable earlier and more accurate diagnoses. This will pave the way for personalized therapeutic strategies for patients with SAIDs.
