Human Endogenous Retroviruses Drive Type-I Interferon Signaling activation in Early Rheumatoid Arthritis

Substantial reactivation of HERVs was observed in both synovial tissues and PBMCs from early RA patients. Differentially expressed HERVs regulate adjacent ISGs expression by providing cis-regulatory elements. Moreover, excessive cytoplasmic HERVs trigger a type I interferon (IFN-I) response through the dsRNA-RIG-I-IRF3-IFN-I axis. Targeting endogenous retroviruses exhibited potential therapeutic benefits in both CIA mouse models and RA patient-derived ex vivo models. Specifically, the IFN-I inducible HERV.MLT2B2, a novel primate-specific retroelement, acts as a key driver of the antiviral gene IFI44L, establishing a positive feedback loop that amplifies IFN-I signaling.