Lipid presentation by the protein C receptor links coagulation with autoimmunity.
Wolfram RufAnne HollerbachJennifer RoyceSvenja RitterDenise G PedrosaThati MadhusudhanSina TeifelMyriam MeineckFriederike HäuserAntje CanisiusT Son NguyenJohannes BraunKai BrunsAnna EtzoldUlrich ZechnerSusanne StrandMarkus RadsakDennis StrandJian-Ming GuJulia Weinmann-MenkeCharles T EsmonLuc TeytonKarl J LacknerWolfram RufPublished in: Science (New York, N.Y.) (2021)
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.
Keyphrases
- cell surface
- toll like receptor
- systemic lupus erythematosus
- immune response
- binding protein
- mouse model
- innate immune
- protein protein
- multiple sclerosis
- amino acid
- inflammatory response
- nuclear factor
- drug induced
- pulmonary embolism
- social media
- preterm birth
- fatty acid
- mesenchymal stem cells
- disease activity
- rheumatoid arthritis
- celiac disease