Spontaneous activation of RNA-sensing pathways in autoimmune disease

• RNA from viral replication intermediates stimulates endosomal/cytoplasmic sensors.
• Autoimmunity develops from mutations in protective cytoplasmic nulceases.
• Genetic studies indicate RNA sensing pathways in autoimmunity.
• Pathogenic stimulatory RNA may come from self or viral sources.

Multiple intracellular RNA sensing innate immune pathways have been linked to autoimmune disease. RNA-related ligands taken up by the endocytic pathway activate TLRs, and affect primarily immune cells. This type of activation is enhanced by nucleic acid-specific antibodies and induces an inflammatory program. In contrast, spontaneous activation of cytoplasmic RNA sensing pathways targets mostly non-hematopoietic tissues and their effect on autoimmune disease is secondary to the release of interferon in the circulation. The fact that pathologies result from spontaneous activation of innate pathways implies that endogenous RNA ligands that might be sensed as pathogenic are commonly found in both immune and non-immune cells.