Innate immune sensing of
nucleic acids provides resistance against
viral infection and is important in the aetiology of
autoimmune diseases. AGS (Aicardi-Goutières syndrome) is a monogenic autoinflammatory disorder mimicking in utero
viral infection of the brain. Phenotypically and immunologically, it also exhibits similarities to SLE (systemic lupus erythaematosus). Three of the six genes identified to date encode components of the
ribonuclease H2 complex. As all six encode
enzymes involved in
nucleic acid metabolism, it is thought that pathogenesis involves the accumulation of
nucleic acids to stimulate an inappropriate innate immune response. Given that AGS is a monogenic disorder with a defined molecular basis, we use it as a model for common
autoimmune disease to investigate cellular processes and molecular pathways responsible for
nucleic-acid-mediated autoimmunity. These investigations have also provided fundamental insights into the biological roles of the
RNase H2
endonuclease enzyme. In the present article, we describe how human
RNase H2 and its role in AGS were first identified, and give an overview of subsequent structural, biochemical, cellular and developmental studies of this
enzyme. These investigations have culminated in establishing this
enzyme as a key genome-surveillance
enzyme required for mammalian
genome stability.