LINE-1 dysregulation: driving autoimmune disorders

Autoimmune diseases refer to a spectrum of disorders in which the host immune system aberrantly attacks self-tissues instead of exerting protective immune functions. Such attacks can target skin, muscles, joints, and even the nervous system. Interestingly, despite the heterogeneity of affected tissues and organs, many autoimmune diseases share core molecular features, including the upregulated expression of interferons (IFNs) and IFN-stimulated genes (ISGs), which reflects robust activation of the host innate immune response. Traditionally, innate immune activation observed in these disorders was considered to be triggered by exogenous pathogen infections. However, accumulating evidence has confirmed the presence of endogenous triggers that drive the pathogenesis of autoimmune diseases. Type 1 long interspersed elements (LINE-1 or L1) are the only known retroelements that can replicate autonomously in human cells. The retrotransposition process of LINE-1 produces diverse molecular products including DNA, RNA, and proteins, and entails multiple key events: the assembly of LINE-1-derived ribonucleoprotein (RNP) complexes, genomic DNA nicking, and de novo insertion of LINE-1 fragments into the host genome. Owing to these biological characteristics, LINE-1 serves as a critical cellular trigger for innate immune activation. This review focuses on the functional association between LINE-1 and autoimmune diseases. We first elaborate on the molecular properties and replication mechanisms of LINE-1, followed by a systematic discussion of the mechanisms by which LINE-1 induces IFN production and innate immune activation. We further summarize the current evidence linking LINE-1 dysregulation to autoimmune pathogenesis, aiming to provide insights and facilitate future research in associated fields.