Interferons in Sjogren’s disease: current status and future prospects

Sjögren's disease (SjD) is a systemic autoimmune disorder marked by chronic immune activation, with a central role attributed to the interferon (IFN) system. The so-called 'IFN signature' at both tissue and peripheral levels has long been recognized as a hallmark of SjD, and recent advances have provided a more detailed molecular understanding of this dysregulation. Nevertheless, the aberrant expression and signaling of type I, II, and, more recently, type III IFNs reflect a complex network of interactions between epithelial and immune cells. This crosstalk is multidirectional, temporospatial, and highly dynamic, shaping the heterogeneity of disease activity, clinical course, and patient phenotypes and endotypes. Therapeutic targeting of IFN pathways has emerged as a major focus in SjD, with several clinical trials providing valuable insight. While preliminary benefits have been overwhelmingly promising, outcomes remain somewhat variable, influenced by factors such as trial design, patient stratification, disease stage, and underlying immunological endotypes. These challenges underscore the need for refined approaches to harness IFN modulation effectively in clinical practice. This review summarizes current knowledge of the three IFN families and their contribution to SjD pathogenesis, while highlighting recent research advancements that underscore their promise as therapeutic targets. By integrating clinical and translational perspectives, we aim to clarify our understanding of the role of IFNs in SjD and provide a framework for future research and therapy development approaches.