Abstract
Objective Neutrophil extracellular traps (NETs) are essential in host defense, but are also linked to inflammation and autoimmunity, including systemic lupus erythematosus (SLE). We recently described that immune complexes (ICs) induce NET formation, promoting lupus-like disease in mice. In the current study, we investigated, for the first time, the role of NETs in human SLE and their association with disease activity and severity.
Methods Levels of NETs (MPO-DNA complexes) were analyzed in plasma from four crosssectional SLE cohorts (n=44-142), one longitudinal SLE cohort (n=47), and healthy individuals (n=100) using ELISA. Type I interferon (IFN) activity was determined using a cell reporter system.
Results SLE patients had elevated levels of NETs in circulation compared to healthy controls (p<0.01). NET levels identified patients with a severe disease phenotype characterized by ICdriven nephritis (p<0.05). Though not associated with current disease activity (p=0.20), levels of NETs were associated with future increase in SLEDAI within three months (OR=1.75, p=0.01), as well as an overall heightened SLEDAI over one year (p<0.01). Finally, levels of NETs were associated with arterial events (OR=5.0, p=0.02) and endothelial cell activation (p<0.001).
Conclusion NET levels are elevated in SLE patients, associated with IC-driven disease. NET levels provide significant clinical value in identifying patients at risk of active disease and/or severe disease, including nephritis and cardiovascular disease, which may allow for early interventions.
