SLE is a debilitating systemic autoimmune disease characterized by the overproduction of pathogenic antibodies to nuclear and cytoplasmic antigens. Nucleic acid sensing endosomal TLRs (TLR7 and 9) detect RNA or DNA-associated macromolecular complexes respectively, leading to the activation of B cells, plasmacytoid dendritic cells (pDCs), neutrophils, as well as other cell types. Autoantigen-activated pDCs and APCs produce high levels of type I interferon (IFN) and pro-inflammatory cytokines, which further promote the development of autoantibodies and other pathogenic mechanisms.  The work proposed in this application will investigate the role of a long non-coding RNA called lincRNA-Eps, that we have identified, which restrains the transcription of type I IFNs and ISGs. We propose to understand the regulation of this lincRNA by TLRs, the mechanisms by which this lincRNA prevents the inappropriate activation of the type I IFN response and the impact of lincRNA-Eps-deficiency on spontaneous autoimmunity as well as TLR driven autoimmunity in vivo. Detailed mechanistic studies of how lncRNAs impact type I IFNs and ISGs and elucidation of their mode of action could provide critical insights that could potentially lead to the development of improved therapeutics for SLE and other autoimmune diseases.