Systemic lupus erythematosis is a chronic autoimmune disease characterized by the loss of tolerance to nuclear antigens and the development of pathogenic autoantibodies, resulting in injury to multiple organ systems. Studies of patients with SLE and work in murine models of lupus have strongly implicated type I IFNs in its pathogenesis. Type I IFNS are composed of up to 13 IFN-alphas and a single IFN-beta, -kappa, -epsilon, and -omega. All of these subtypes bind to the type I IFN receptor to mediate their actions, but little is known about their individual biological properties. IFN-kappa is constitutively produced by keratinocytes and also produced by DCs and macrophages. We have recently begun characterizing mice in which the IFN-kappa gene has been deleted. Surprisingly, mice lacking IFN-kappa are protected from viral infection, suggesting that its function is distinct from the other subtypes of IFN. We propose that IFN-kappa binding to the type IFN receptor results in distinct activation of the receptor as compared to other subtypes of IFN, which may have important implications for its activity in SLE. Studies outlined in this proposal will compare the activities of IFN-kappa and IFN-a and evaluate the function of IFN-kappa during SLE pathogenesis.