Nucleic acid triggers of autoimmunity and autoinflammation

The key role of nucleic acid sensing receptors in the development of autoimmune and autoinflammatory diseases is becoming increasingly apparent. Activation of these sensors has been attributed to the failure of professional scavenger cells to adequately clear cell debris, in many cases due to defective scavenger receptors. However, as now summarized in this review, numerous gain-of-function mutations in the nucleic acid sensing receptors, or in molecules that regulate sensor activity, have now been evaluated in gene-targeted murine strains, and critical components of their downstream pathways have been identified as therapeutic targets. In addition, we are beginning to understand how DNases and RNases play crucial roles in both generating and eliminating the distinct ligands that engage the various nucleic acid sensors. Murine models of disease have further provided important insights regarding the function of and synergy between individual endosomal and cytosolic receptors, as well as cell type restricted functions.