Targeted therapeutics in SLE: emerging strategies to modulate the interferon pathway

Systemic lupus erythematosus (SLE) is a prototypic autoimmune disease characterized by impaired immune tolerance, resulting in the generation of pathogenic autoantibodies and immune complexes. Although autoreactive B lymphocytes have been the first targets for biologic therapies in SLE, the importance of the innate immune system, and in particular, pathways involved in interferon (IFN) signaling, has emerged. There are now data supporting a central role for a plasmacytoid dendritic cell-derived type I IFN pathway in SLE, with a number of biologic therapeutics and small-molecule inhibitors undergoing clinical trials. Monoclonal antibodies targeting IFN-α have completed phase II clinical trials, and an antibody against the type I IFN receptor is entering a phase III trial. However, other IFNs, such as IFN gamma, and the more recently discovered type III IFNs, are also emerging as targets in SLE; and blockade of upstream components of the IFN signaling pathway may enable inhibition of more than one IFN subtype. In this review, we discuss the current understanding of IFNs in SLE, focusing on emerging therapies

Translating nucleic acid-sensing pathways into therapies

Nucleic acid sensing initiates the immune defense against viruses and other pathogens. A hallmark consequence of nucleic acid receptor activation is the release of interferons (IFN), which promote protective immune responses via the expression of multiple interferon stimulated genes (ISG). A similar ISG signature is also found in autoinflammatory and autoimmune conditions, indicating that chronic activation of nucleic acid sensing pathways may contribute to these diseases. At both ends of this spectrum nucleic acid sensors and their signaling mediators emerge as highly attractive drug targets. Agonists are being developed as anti-infectives, immune stimulants or vaccine adjuvants, and antagonists as anti-inflammatory immune modulators. Here we review how nucleic acid sensing pathways are currently being targeted pharmacologically. We propose how the emerging wealth of molecular, mechanistic and clinical insight can be leveraged towards novel therapies of infections, cancer, autoimmune and autoinflammatory disorders, and how new agonists and antagonists of nucleic acid sensing pathways will in turn reinform our mechanistic understanding of these complex diseases