Grant: Team Grant: E-Rare Joint Transnational Call

Autoinflammatory diseases (AID) are a group of devastating systemic inflammatory syndromes characterized by seemingly unprovoked episodes of severe inflammation without signs of classical autoimmunity. The general prevalence of AID is below 1:1,000,000 individuals. As the genes mutated in AID are increasingly being mapped, inflammasome signaling and the cytoskeletal network are emerging as key mechanisms responsible for AID. Excess interleukin (IL)-1beta production has a primary pathogenic role in select AID (exemplified by CAPS), but IL-1 neutralization therapies are ineffective or only partially effective in the majority of AID patients. Thus, there is a high unmet need for development of novel therapies to treat IL-1-refractory AID and devastating AID-associated complications such as macrophage activation syndrome (MAS). Our consortium has classified a subset of AID patients with selective and highly elevated IL-18 and MRP8/14 in circulation. These inflammatory mediators are hypothesized to support a vicious inflammatory cycle in anti-IL-1-refractory AID. The consortium has at its disposal a unique set of preclinical therapeutic agents, as well as cellular and in vivo models of non-classical AID that will be exploited to address the therapeutic potential of IL-18 and MRP neutralization strategies in single and combination regimens. Finally, we will address how cytoskeleton dynamics and immune cell activation contribute to IL-18 and MRP8/14 secretion in AID mouse models using cutting-edge in vivo imaging.