An Update on Autoinflammatory Diseases: Interferonopathies

Type I interferons (IFNαβ) induce the expression of hundreds of genes; thus, it is unsurprising that the initiation, transmission, and resolution of the IFNαβ-mediated immune response is tightly controlled. Mutations that alter nucleic acid processing and recognition, ablate IFNαβ-specific negative feedback mechanisms, or result in dysfunction of the proteasome system can all induce pathogenic IFNαβ signalling and are the focus of this review.

Recent advances have delineated the precise cytoplasmic mechanisms that facilitate self-DNA to be recognised by cGAS and self-RNA to be recognised by RIG-I or MDA-5. This helps clarify interferonopathies associated with mutations in genes which code for DNase-II and ADAR1, among others. Similarly, loss of function mutations in Pol α, which lowers the presence of antagonistic ligands in the cytosol, or gain of function mutations in RIG-I and MDA-5, result in increased propensity for receptor activation and therefore IFNαβ induction. As the aetiology of monogenic autoinflammatory diseases are uncovered, novel and sometimes unsuspected molecular interactions and signalling pathways are being defined. This review covers developments that have come to light over the past 3 years, with reference to the study of interferonopathies.