ABSTRACT
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. Although autoimmune aPL cross react with various coagulation regulatory proteins, lipid-reactive aPL, including those derived from patients with COVID-19, recognize the endolysosomal phospholipid lysobisphosphatidic acid presented by the cell surface-expressed endothelial protein C receptor. 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 aPL derived from patients with COVID-19 in mice and the aPL-induced proinflammatory and prothrombotic activation of monocytes. The induction of experimental APS is dependent on the nicotinamide adenine dinucleotide phosphate (NADPH) oxidase complex, and NAPc2 suppresses monocyte endosomal reactive oxygen species production requiring the TF cytoplasmic domain and interferon-α secretion from dendritic cells. Latent infection with murine cytomegalovirus 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.
Subject(s)
Antiphospholipid Syndrome , COVID-19 , Virus Diseases , Humans , Animals , Mice , Antibodies, Antiphospholipid , Thromboplastin/metabolism , Mice, Inbred MRL lpr , Antiphospholipid Syndrome/complications , Phospholipids , Anticoagulants , COVID-19/complications , Virus Diseases/complicationsABSTRACT
Evidence-based program resources (EBPR) websites evaluate behavioral health programs, practices or policies (i.e., interventions) according to a predetermined set of research criteria and standards, usually resulting in a summary rating of the strength of an intervention's evidence base. This study is a mixed-methods analysis of the peer-reviewed academic literature relating to the influence of EBPRs on clinical practice and policy in the behavioral health field. Using an existing framework for a scoping review, we searched for research articles in PubMed, Web of Science, SCOPUS, and ProQuest that were published between January 2002 and March 2022, referenced an EBPR or multiple EBPRs, and presented data showing the influence of one or more EBPRs on behavioral health. A total of 210 articles met the inclusion criteria and were classified into five distinct categories of influence, the most important of which was showing the direct impact of one or more EBPRs on behavioral health (8.1% of articles), defined as documenting observable changes in interventions or organizations that are at least partly due to information obtained from EBPR(s). These included impacts at the state legislative and policy-making level, at the community intervention level, provider agency level, and individual practitioner level. The majority of influences identified in the study were indirect demonstrations of how EBPRs are used in various ways. However, more studies are needed to learn about the direct impact of information from EBPRs on the behavioral health field, including impact on clinician practice and treatment outcomes for consumers.
Subject(s)
Learning , Policy , Humans , Policy MakingABSTRACT
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.
