Autoantibodies From Connective Tissue Diseases Penetrate Cells and Exert Functional Properties

Antinuclear antibodies (ANAs) are a hallmark of connective tissue diseases (CTDs) and serve as robust diagnostic biomarkers. Because their cognate antigens are intracellular, ANAs have long been considered non-pathogenic in CTDs. Here, using systemic sclerosis (SSc) associated anti-topoisomerase I antibodies (ATAs) as a model, we provide data challenging this view. We show that ANAs enter living cells, accumulate in nuclei, and engage their intracellular antigen. Nuclear ATAs inhibit topoisomerase I enzymatic activity, induces DNA damage, fibrosis, and, through the STING pathway, activates type I interferon production. We further identify neonatal Fc receptor (FcRn)-dependent intracellular trafficking as a key determinant of ANAs nuclear access and demonstrate that pharmacological FcRn blockade impairs ATAs functionality. These findings reveal a previously unrecognized intracellular effector function of ANAs and establish a mechanistic framework by which ANAs may directly contribute to tissue injury in CTDs.