Mutations in innate immune genes can cause autoinflammatory disease. A particular focus in this area has been the inflammasome protein complex which generates the cytokines IL-1b and IL-18. Specifically, we found mutations that activate the Pyrin inflammasome in a dominantly inherited skin disease we called PAAND, leading to successful therapy by blocking IL-1b. Additionally, the team identified novel mutations in the NLRC4 inflammasome that trigger IL-18 production with early onset inflammatory bowel disease.
A separate class of autoinflammatory diseases are associated with increased production of type I IFN, for example with mutations that activate the cGAS/Sting cytoplasmic DNA sensor system. We have now implicated this same system in the progression of amyotrophic lateral sclerosis (ALS). It turns out that TDP-43, which is normally a nuclear protein, mislocalises to mitochondria in patients with ALS, releasing mitochondrial DNA and triggering neuroinflammation.