Figure 1.

Type I Interferonopathies with neuroinflammation may arise from the gain of function mutations in genes encoding intracellular sensors and adaptors (as IFIH1 gene coding for MDA5 in Aicardi-Goutières syndrome (AGS), and STING in STING-associated vasculopathy with onset in infancy (SAVI)) or loss of function mutations in enzymes involved in nucleotide metabolism which causes an increase of cytosolic DNA (as in AGS due to TREX1 or SAMHD1 mutations), RNA/DNA hybrids (as in AGS due to one of the endonucleases of the RNAseH2 complex) or RNA (as in DADA disease, due to ADAR1 gene). Both mechanisms result in an excessive IRF3-mediated transcription of type I interferons (IFNα/β), which trigger an autocrine and/or paracrine loop of the hyperinflammatory state through IFN-α/β receptor (IFNAR) activation and IFN stimulated genes (ISGs) transcription.