In addition to their protective role against microbial pathogens and neoplastic cells, high levels of circulating type I Interferon are associated with the development of auto-immune diseases in humans. We have used a forward genetic approach to identify novel negative regulators of the innate response to cell-free DNA whose loss-of-function is known to be associated with systemic inflammation and auto-immunity. We are exploring the molecular mechanisms underlying the role of these negative regulators in type I Interferon signaling.