Regulation of Nucleic Acid Sensing Toll-Like Receptors in Systemic Lupus Erythematosus

Autoimmune disease is an aberrant response of the immune system to self. Unlike the adaptive immune system, the innate immune system is not selected during development and was originally thought to inherently discriminate between host and foreign molecular structures (Janeway, 1989). This is true for many innate immune receptor ligands including lipopolysaccharide, which is only synthesized by Gram-negative bacteria. However, some innate immune receptors detect nucleic acids that are shared between microbes and the host. Immune complexes containing nucleic acids are a hallmark of Systemic Lupus Erythematosus (SLE), and the nucleic acid sensing Toll-like receptors (TLRs) respond to the DNA and RNA within these complexes thereby contributing to disease. Defects in regulation of this class of innate immune receptors likely play a key role in precipitation of disease. Here we review nucleic acid sensing TLRs in SLE and recent advances in our understanding of the regulatory mechanisms governing TLR activity. Since breakdown of regulatory mechanisms controlling response of nucleic acid-sensing TLRs likely contributes to development of SLE, targeting specific proteins in these regulatory pathways has the potential to block nucleic acid-driven autoimmune inflammation.