Lipid presentation by the protein C receptor links coagulation with autoimmunity

Area of Science:

• Immunology
• Autoimmunity
• Vascular Biology

Background:

• Antiphospholipid antibodies (aPLs) are key drivers of severe autoimmune conditions, including vascular pathologies and pregnancy complications.
• The precise cell surface targets and signaling mechanisms of aPLs remain incompletely understood, hindering therapeutic development.

Purpose of the Study:

• To identify the specific cell surface antigen recognized by aPLs.
• To elucidate the role of this antigen in aPL-mediated thrombosis and inflammatory signaling.
• To evaluate the therapeutic potential of targeting this antigen in a preclinical model.

Main Methods:

• Identification of endosomal lysobisphosphatidic acid (LBPA) presented by the endothelial protein C receptor (EPCR) as a target antigen.
• Analysis of aPL engagement with EPCR-LBPA on innate immune cells.
• Assessment of interferon- and toll-like receptor 7-dependent B1a cell expansion and autoantibody production.
• Pharmacological inhibition of EPCR-LBPA signaling in a mouse model of systemic lupus erythematosus.

Main Results:

• aPLs recognize the EPCR-LBPA complex on innate immune cells, initiating endosomal inflammatory signaling.
• This interaction sustains B1a cell expansion and autoantibody production, perpetuating a self-amplifying autoimmune loop.
• Pharmacological interruption of EPCR-LBPA signaling significantly attenuated aPL-induced pathologies and autoimmunity in a mouse model.

Conclusions:

• The EPCR-LBPA complex is a critical cell surface target for pathogenic aPLs.
• Targeting the EPCR-LBPA interaction offers a promising therapeutic strategy for antiphospholipid syndrome and related autoimmune diseases.
• This finding reveals a novel mechanism for autoimmune disease perpetuation involving innate immune cooperation with adaptive immunity.