Different studies have demonstrated that neutrophil extracellular traps (NETs) may be involved in the pathophysiology of both ANCA-associated vasculitis (AAV) and systemic lupus erythematosus (SLE). AAV and SLE are clinically and pathologically divergent autoimmune diseases with different autoantibodies. However, the respective autoantigens recognized in AAV and SLE have been shown to be an intricate part of NETs. Therefore, we hypothesized that the mechanisms of NET formation and the composition of NETs might be distinct between AAV and SLE.To investigate this hypothesis, we directly compared AAV- and SLE-induced NET formation, by stimulating healthy neutrophils with AAV (n=80) and SLE (n=59) sera.Both AAV and SLE patients had excessive NET formation which correlated with disease activity(r=0.5;p<0.0001 resp. r=0.35;p<0.01). We observed lytic NET formation in AAV after hours versus rapid non-lytic NET formation coinciding with clustering of neutrophils in SLE within minutes. AAV-induced NET formation was triggered independent of (ANCA)-IgG whereas SLE-immune complexes (ICx) induced NET formation through FcγR-signaling. AAV-induced NET formation was dependent of reactive oxygen species and peptidyl-arginine-deaminases and was enriched for citrullinated histones(23±2%), all in contrast to SLE-induced NETs. SLE-induced NETs had immunogenic properties including NET-bound HMGB1(30±3%), enrichment for oxidized mtDNA, and were involved in ICx formation.In conclusion, morphology, kinetics, induction pathways and composition of excessive NET formation are all intrinsically distinct in AAV compared to SLE. Recognizing the diversity of NET formation between AAV and SLE provides a better understanding of the pathophysiological role of NETs in these different autoimmune diseases. This article is protected by copyright. All rights reserved.
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