Kastner/Stone/Canna

Project Title

IL-18 in the pathogenesis of PSTPIP1-related autoinflammatory diseases

NIH Mentors

Dan Kastner, Deborah Stone

Penn Mentor 

Scott Canna

Project Details

IL-18 is canonically a cytokine induced in macrophages, activated by the inflammasome, and acting on NK and T cells to enhance Interferon-gamma (IFN-g) production. Clinically, extremely high levels of total IL-18, and detectable free IL-18, have been associated with susceptibility to an IFN-g-mediated cytokine storm syndrome called Macrophage Activation Syndrome (MAS). Pathogenic variants in the inflammasome-related gene PSTPIP1 cause a spectrum of autoinflammatory phenotypes that include severe acne, arthritis, pyoderma gangrenosum, neutropenia, and hepatosplenomegaly. A recent collaboration between the Kastner and Canna groups identified that patients with PSTPIP1-related disease have very high total IL-18 (and detectable free IL-18) but do not develop MAS. This project aims to understand the origins of excess IL-18 in response to PSTPIP1 mutations and how this cytokine drives their unique immunopathology. It will focus on exploring non-myeloid inflammasome activation, unique mechanisms of cell death, unique effector populations, and potentially therapeutic potential of IL-18 blockade.