Aicardi-Goutières syndrome and the type I interferonopathies

Our work in this area started with the Mendelian inflammatory disorder Aicardi-Goutières syndrome (AGS)(see Video 1 for one family’s perspective on the condition). Clinical and genetic studies of this severe disease helped to expand the phenotypic spectrum associated with mutations in the AGS-related genes, define a cell-intrinsic mechanism for the initiation of autoinflammation / autoimmunity by stimulatory nucleic acids, and further emphasise the importance of type I interferon processing in the pathogenesis of certain non-Mendelian disorders, particularly systemic lupus erythematosus. Since then, a combination of clinical, genetic and immunological perspectives has led us to suggest that monogenic disorders associated with an upregulation of type I interferons represent a novel set of inborn errors of immunity due to abnormal sensing, inappropriate stimulation, or defective negative regulation of the type I interferon system – the so-called type I interferonopathies. There is a clear unmet clinical need for treatments in this area - as an example, see: Video 2 demonstrating the progressive nature of a motor disturbance, in the absence of intellectual decline, in a young patient with disease due to ADAR1 dysfunction; and Video 3 relating to a patient with a dominantly inherited variant in MDA5 / IFIH1, again in the absence of intellectual difficulties. The scientific insights so far obtained suggest the possibility of therapies to block nucleic acid driven inflammation (for example, the JAK1/2 inhibitor ruxolitinib – see Video 4 adapted from Kothur et al. Neurology 2018;90:289-291; N Engl J Med2018 6;379(23):2275-7), and have important implications for fundamental research into mechanisms of self / non-self discrimination and viral immunity. As such, our current work focuses on the identification and characterization of genes and proteins predisposing to these diseases, and the ways in which we might best treat them. [Videos shown with permission].