Type I Interferonopathies: Genetic and Mechanistic Advances Refine Diagnosis and Pave Way for Targeted Therapies

Type I interferonopathies represent a group of severe monogenic autoinflammatory diseases characterized by inappropriate activation of type I interferon signaling. These conditions often lead to significant morbidity and mortality due to overlapping neuroinflammatory, cutaneous, and systemic manifestations. Historically, understanding of their molecular basis was limited, hindering precise diagnosis and the development of targeted therapies. Current standard-of-care often involves symptomatic management, which falls short in addressing the underlying immune dysregulation. This review addresses the critical need for an updated synthesis of genetic and mechanistic advances to guide improved diagnostic and therapeutic strategies.

This comprehensive review synthesizes 15 years of research on type I interferonopathies, integrating recent genetic and mechanistic discoveries. It aims to update the field's understanding, outline practical diagnostic approaches, and highlight current and emerging targeted therapeutic strategies. The authors systematically analyzed a broad range of scientific literature to provide an updated overview, focusing on the molecular bases of these disorders, refinements in their classification, and advancements in therapeutic development. The review's scope encompasses the evolution of the concept from initial descriptions to current therapeutic perspectives, offering a consolidated resource for clinicians and researchers.

Multiple pathogenic mechanisms underlying type I interferonopathies have been identified, including abnormalities in nucleic acid metabolism or sensing, constitutive activation of innate immune pathways, proteasome dysfunction, endosomal Toll-like receptor hyperactivation, and impaired negative regulation of IFNAR signaling. These diverse mechanisms converge on the common outcome of heightened type I interferon activity, driving the characteristic neuroinflammatory, cutaneous, and systemic manifestations. Advances in understanding the molecular basis have significantly refined the classification of these disorders, moving towards a more precise, mechanism-based approach. This enhanced understanding has also led to improved diagnostic strategies, allowing for earlier and more accurate identification of affected individuals. > These insights are paving the way for more precise, mechanism-based treatments, offering promising perspectives for patient management despite the persistent severity of these disorders, marking a significant shift from symptomatic to targeted therapeutic interventions.