RNA/DNA sensing in SLE—Toll-like receptors and beyond

Systemic lupus erythematosus (SLE) is a chronic systemic autoimmune disease characterized by overactivation of the type I interferon (IFN) system, driven by deregulation of pathways that recognize and respond to nucleic acids. Circulating autoantibodies targeting nucleic acids and nuclear proteins from patients with SLE have been shown to have adjuvant-like properties that can directly or indirectly hyper-stimulate autoreactive lymphocytes. These adjuvant-like complexes are composed of DNA and/or RNA-containing immune complexes (ICs) activate immune cells via engagement of the innate immune nucleic acid sensors Toll-like receptors (TLR) 7, 8, and TLR9, driving production of interferon-alpha (IFN-α) and other inflammatory cytokines. In addition to nucleic-acid sensing TLRs, intracellular RNA, and DNA sensing pathways have recently come to the fore as being important in triggering IFN release and inflammation in human lupus. This chapter will focus on the role of these two families of RNA/DNA sensors and how they contribute to the susceptibility, initiation, and exacerbation of SLE.