Lipid presentation by the protein C receptor links coagulation with autoimmunity

作者信息Nadine Müller-Calleja, Anne Hollerbach, Jennifer Royce, Svenja Ritter, Denise Pedrosa, Thati Madhusudhan, Sina Teifel, Myriam Meineck, Friederike Häuser, Antje Canisius, T Son Nguyen, Johannes Braun, Kai Bruns, Anna Etzold, Ulrich Zechner, Susanne Strand, Markus Radsak, Dennis Strand, Jian-Ming Gu, Julia Weinmann-Menke, Charles T Esmon, Luc Teyton, Karl J Lackner, Wolfram Ruf
PMID33707237
期刊Science
发布时间2021-03-12
DOI10.1126/science.abc0956

摘要

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.

实验方法

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