Type I interferonopathies: 15 years after the concept-news and views

Genetic autoinflammatory conditions constitute an increasing field. Among them, type I interferonopathies (IFNp-I) were conceptualized 15  years ago as inborn errors of immunity due to chronic activation of the type I interferon (IFN-I) signalling pathway. Here, we provide recent insights in genetic mechanisms, clinical phenotypes and therapeutic options for these severe and rare disorders.

We will cover the novel findings into disease mechanisms, particularly the role of PTP1B in STING and IFNAR signalling, as well as the contribution of endosomal TLR pathways. We will also discuss the expanding phenotypic spectrum highlighted by recent case reports and cohort studies, together with the topic of clinical expressivity, including clinical non-penetrance, and possible mechanistic explanations such as monoallelic expression, the STING HAQ haplotype, and innovative approaches to characterise disease variability. Finally, we discuss current targeted therapeutic approaches for these disabling conditions, as well as potential new treatments for the future.

Overall, these findings highlight the need to consider these rare diseases across a wide range of clinical phenotypes. Advances in next-generation sequencing have enabled a genetic diagnosis in suspected cases and the implementation of targeted treatments, thereby reducing diagnostic uncertainty and providing the possibility of genetic counselling.