Autoantibodies From Connective Tissue Diseases Penetrate Cells and Exert Functional Properties
Chepy, A.; Thiesen, C.; Martel, M.-E.; Aspari, M.; Vivier, S.; Mikkelsen, J. H.; Holm, E.; Morische, S. M.; Naeser, E.; Sottiaux, J.; Duhamel, M.; Sondergaard, K.; Petersen, S. B.; Mistretta, M.; Secq, M.; Hvid, M.; Keller, J. G.; Abraham, D.; Hatipoglu, E.; Chauvet, C.; Guilbert, L.; Jensen, E. G.; Paludan, S. R.; Andersen, C. B. F.; Bongiovanni, A.; Hachulla, E.; Salzet, M.; Kalucka, J. M.; Knudsen, B. R.; Dubucquoi, S.; Greisen, S.; Launay, D.; Tesauro, C.; Tardivel, M.; Deleuran, B.; Sobanski, V.
Show abstract
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.
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