Lipid presentation by the protein C receptor links coagulation with autoimmunity
Nadine Müller‐Calleja, Anne Hollerbach, Jennifer Royce, Svenja Ritter, Denise Pedrosa, Thati Madhusudhan, Sina Teifel, Myriam Meineck, Friederike Häuser, Antje Canisius, Thanh‐Son Nguyen, Johannes Braun, Kai Bruns, Anna Etzold, Ulrich Zechner, Susanne Strand, Markus P. Radsak, Dennis Strand, Jian-Ming Gu, Julia Weinmann‐Menke, Charles T. Esmon, Luc Teyton, Karl J. Lackner, Wolfram Ruf
Abstract
Antiphospholipid antibodies (aPLs) cause severe autoimmune disease characterized by vascular pathologies and pregnancy complications. Here, we identify endosomal lysobisphosphatidic acid (LBPA) presented by the CD1d-like endothelial protein C receptor (EPCR) as a pathogenic cell surface antigen recognized by aPLs for induction of thrombosis and endosomal inflammatory signaling. The engagement of aPLs with EPCR-LBPA expressed on innate immune cells sustains interferon- and toll-like receptor 7-dependent B1a cell expansion and autoantibody production. Specific pharmacological interruption of EPCR-LBPA signaling attenuates major aPL-elicited pathologies and the development of autoimmunity in a mouse model of systemic lupus erythematosus. Thus, aPLs recognize a single cell surface lipid-protein receptor complex to perpetuate a self-amplifying autoimmune signaling loop dependent on the cooperation with the innate immune complement and coagulation pathways.