Autoantibodies against neutrophils extracellular traps and its association with antiphospholipid syndrome clinical manifestations: a large cohort study

Abstract

Antiphospholipid syndrome (APS) is an autoimmune thromboinflammatory disorder characterized by recurrent arterial or venous thrombosis as well as pregnancy loss combined with the persistence of antiphospholipid antibodies (aPL). Although these antibodies have been suggested to activate endothelial cells, monocytes, and platelets, and to disrupt coagulation and fibrinolytic pathways, aPL are regularly detected in individuals without any clinical manifestations, making them inadequate biomarkers of APS. Indeed, treatment is typically not initiated in aPL-positive individuals until they have had their first thrombotic event. Furthermore, aPL are relatively poor predictors of outcomes even after that first thrombotic event. Some patients with APS go into remission with anticoagulation, while others progress in the form of recurrent thrombosis, pregnancy morbidity, and end-organ damage (kidney, heart, etc). A potential breakthrough in the field is the implication of neutrophils and neutrophil extracellular traps (NETs) in the pathogenesis of APS. NETs are prothrombotic tangles of DNA and microbicidal protein released by activated neutrophils. Studies have demonstrated that: (1) aPL engage neutrophils to trigger NETosis; (2) NETs circulate at elevated levels in the blood of patients with APS; (3) APS blood degrades NETs poorly; and-with special relevance to this proposal-(4) patients with APS develop autoantibodies to NETs themselves. Despite these intriguing data, the antigen specificity, function, and prognostic significance of anti-NET autoantibodies in APS have not been adequately investigated. The overarching hypothesis guiding this proposal is that anti-NET autoantibodies are key drivers of thrombotic risk in APS. (AU)