Our research investigates the detection of nucleic acids by the innate immune system. Microbial nucleic acids are a common feature sensed by our immune system to initiate protective responses; however, the detection of host-derived nucleic acids poses the risk of self-recognition and autoimmune disease. A specific subset of Toll-like receptors, specializing in nucleic acid detection, localizes and signals from endolysosomal compartments, a setup vital for discriminating self from foreign nucleic acids. We are mapping the specific trafficking pathways that deliver these receptors to their signaling compartments and identify sorting defects that lead to hyperactive signaling and autoreactive immune responses. Patients with mutations in these pathways develop autoimmune disease at a very young age.