Lipid presentation by the protein C receptor links coagulation with autoimmunity.

Animals Antibodies, Antiphospholipid / biosynthesis Antigen Presentation Autoantibodies / biosynthesis Autoimmunity Blood Coagulation / immunology Disease Models, Animal Embryo Loss / immunology Endosomes / immunology Endothelial Protein C Receptor / genetics Humans Immunity, Innate Lupus Erythematosus, Systemic / blood Lysophospholipids / immunology Mice Mice, Mutant Strains Monoglycerides / immunology Sphingomyelin Phosphodiesterase / metabolism Thrombosis / immunology Toll-Like Receptor 7 / immunology

Journal

Science (New York, N.Y.)

ISSN: 1095-9203

Titre abrégé: Science

Pays: United States

ID NLM: 0404511

Informations de publication

Date de publication:
12 03 2021

Historique:

received: 06 04 2020

revised: 15 09 2020

accepted: 15 01 2021

entrez: 12 3 2021

pubmed: 13 3 2021

medline: 31 3 2021

Statut: ppublish

Résumé

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.

Identifiants

DOI: 10.1126/science.abc0956 PMID: 33707237 PMC: PMC9014225

pubmed: 33707237

pii: 371/6534/eabc0956

doi: 10.1126/science.abc0956

pmc: PMC9014225

mid: NIHMS1781115

pii:

doi:

Substances chimiques

Antibodies, Antiphospholipid 0

Autoantibodies 0

Endothelial Protein C Receptor 0

Lysophospholipids 0

Monoglycerides 0

Procr protein, mouse 0

Toll-Like Receptor 7 0

bis(monoacylglyceryl)phosphate 0

Sphingomyelin Phosphodiesterase EC 3.1.4.12

Types de publication

Journal Article Research Support, N.I.H., Extramural Research Support, Non-U.S. Gov't

Langues

eng

Sous-ensembles de citation

Subventions

Organisme : NHLBI NIH HHS

ID : R01 HL060742

Pays : United States

Organisme : NHLBI NIH HHS

ID : UM1 HL120877

Pays : United States

Commentaires et corrections

Type : CommentIn

Informations de copyright

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