Targeting the tissue factor coagulation initiation complex prevents antiphospholipid antibody development

Item Type:	Article
Title:	Targeting the tissue factor coagulation initiation complex prevents antiphospholipid antibody development
Creators Name:	Mueller-Calleja, N. and Grunz, K. and Nguyen, T.S. and Posma, J. and Pedrosa, D. and Meineck, M. and Hollerbach, A. and Braun, J. and Muth, S. and Schild, H. and Saar, K. and Hübner, N. and Krishnaswamy, S. and Royce, J. and Teyton, L. and Lemmermann, N.A. and Weinmann-Menke, J. and Lackner, K.J. and Ruf, W.
Abstract:	Antiphospholipid antibodies (aPL) in primary or secondary antiphospholipid syndrome (APS) are a major cause for acquired thrombophilia, but specific interventions preventing autoimmune aPL development are an unmet clinical need. While autoimmune aPL cross-react with various coagulation regulatory proteins, lipid-reactive and COVID-19 patient-derived aPL recognize the endo-lysosomal phospholipid lysobisphosphatidic acid (LBPA) presented by the cell surface expressed endothelial protein C receptor (EPCR). This specific recognition leads to complement-mediated activation of tissue factor (TF) dependent proinflammatory signaling and thrombosis. Here we show that specific inhibition of the TF coagulation initiation complex with nematode anticoagulant protein c2 (NAPc2) prevents the prothrombotic effects of COVID-19 patient-derived aPL in mice and the aPL-induced proinflammatory and prothrombotic activation of monocytes. The induction of experimental APS is dependent on the NAPDH oxidase complex and NAPc2 suppresses monocyte endosomal reactive oxygen species production requiring the TF cytoplasmic domain and IFNa secretion from dendritic cells. Latent infection with murine cytomegalovirus virus causes TF cytoplasmic domain-dependent development of persistent aPL and circulating phospholipid-reactive B1 cells, which is prevented by short term intervention with NAPc2 during acute viral infection. In addition, treatment of lupus prone MRL-lpr mice with NAPc2, but not with heparin, suppresses dendritic cell activation in the spleen, aPL production and circulating phospholipid-reactive B1 cells and attenuates lupus pathology. These data demonstrate a convergent TF-dependent mechanism of aPL development in latent viral infection and autoimmune disease and provide initial evidence that specific targeting of the TF initiation complex has therapeutic benefits beyond currently used clinical anticoagulant strategies.
Keywords:	Antiphospholipid Antibodies, Anticoagulants, Antiphospholipid Syndrome, COVID-19, Inbred MRL lpr Mice, Phospholipids, Thromboplastin, Virus Diseases, Animals, Mice
Source:	Blood
ISSN:	0006-4971
Publisher:	American Society of Hematology
Volume:	143
Number:	12
Page Range:	1167-1180
Date:	21 March 2023
Official Publication:	https://doi.org/10.1182/blood.2023022276
PubMed:	View item in PubMed

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