A large body of research aimed at defining genes contributing to lupus pathogenesis has focused on cytokines and, among them, those encoding the pleiotropic type I and type II interferons (IFNs) have been shown to be key pathogenic effectors. In this proposal, we outline experiments in mouse lupus models to further dissect the mechanisms by which type I IFNs (IFN-alpha/beta) exert their adverse effects, and to devise means to curtail their activity. The hypotheses to be addressed are: a) IFNAR1 deletion reduces lupus development in spontaneous models with diverse genetic abnormalities and disease severity, and a biological blocker of this receptor is effective when applied post-developmentally and at clinically- relevant stages; b) IFN-beta production is required for the IFN-alpha-mediated effects, IFN-alpha/beta and IFN-gamma act coordinately to cause full disease expression, and high levels of the newly identified IFN-lambdas can promote disease in the absence of IFN-alpha/beta or IFN-gamma signaling; c) excessive activation and generation of plasmacytoid dendritic cells (pDCs), the major IFN-alpha/beta producers, are central abnormalities in disease pathogenesis, and d) at the early disease phase, IFN-alpha/beta production and the ensuing autoimmune responses are initiated by endogenous apoptotic materials acting in a TLR-independent pathway, while at the later disease phases, these materials, complexed with autoantibodies, propagate and amplify IFN-alpha/beta production in a TLR-dependent pathway. These studies will advance our knowledge of the mechanisms by which IFNs promote systemic autoimmunity and may contribute to the development of novel therapies for lupus and other autoimmune diseases. ? ? ?
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