Bone stresses out cartilage in OA

Abstract

250 | mAY 2021 | volume 17 OrIgInAL ArTICLe Müller-Calleja, N. et al. Lipid presentation by the protein C receptor links coagulation with autoimmunity. Science 371, eabc0956 (2021) Mice that had defective EPCR trafficking ... were protec\xad ted from fetal loss and thrombosis Antiphospholipid antibodies (aPLs) are associated with various autoimmune diseases, including antiphospholipid syndrome (APS) and systemic lupus erythematosus. The pathogenic effects of these antibodies include activation of coagulation pathways (causing thrombosis, stroke and pregnancy complications) and the induction of pro-inflammatory pathways (promoting autoimmunity). In a new study, researchers have identified a lipid–protein target of aPLs that links both these downstream effects. “Prior research had not been able to clearly separate the contributions of lipid and protein reactivity of aPLs to the pathology of APS,” says Karl Lackner, co-corresponding author on the study. “The starting point for this investigation was our finding that cardiolipin-reactive aPLs, previously considered non-pathogenic, and β2GPI-crossreactive aPLs apparently activated a similar cell signalling pathway in monocytes that involved coagulation and complement components and led to thrombosis,” explains Lackner. By employing various tools, including conformation-specific antibodies and genetically modified mice, the researchers implicated endothelial protein C receptor (EPCR) as a cell surface target for aPLs. Detailed analyses found that lipid-reactive aPLs bound to EPCR in complex with lysobisphosphatidic acid (LBPA), which resulted in aPL internalization and activation of tissue factor-mediated coagulation in a process involving recruitment and activation of the cell surface molecule acidic sphingomyelinase (ASM). “Unexpectedly, the identified signalling mechanism was also responsible for the development of A U TO I M M U n I T Y