Autoinflammatory disorders are sterile inflammatory conditions characterized by 
episodes of early-onset fever and disease-specific patterns of organ 
inflammation. Recently, the discoveries of monogenic disorders with strong type 
I interferon (IFN) signatures caused by mutations in proteasome degradation and 
cytoplasmic RNA and DNA sensing pathways suggest a pathogenic role of IFNs in 
causing autoinflammatory phenotypes. The IFN response gene signature (IGS) has 
been associated with systemic lupus erythematosus (SLE) and other autoimmune 
diseases. In this review, we compare the clinical presentations and pathogenesis 
of two IFN-mediated autoinflammatory diseases, CANDLE and SAVI, with Aicardi 
Goutières syndrome (AGS) and monogenic forms of SLE (monoSLE) caused by 
loss-of-function mutations in complement 1 (C1q) or the DNA nucleases, DNASE1 
and DNASE1L3. We outline differences in intracellular signaling pathways that 
fuel a pathologic type I IFN amplification cycle. While IFN amplification is 
caused by predominantly innate immune cell dysfunction in SAVI, CANDLE, and AGS, 
autoantibodies to modified RNA and DNA antigens interact with tissues and immune 
cells including neutrophils and contribute to IFN upregulation in some SLE 
patients including monoSLE, thus justifying a grouping of "autoinflammatory" and 
"autoimmune" interferonopathies. Understanding of the differences in the 
cellular sources and signaling pathways will guide new drug development and the 
use of emerging targeted therapies.