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Intrinsically Distinct Role of Neutrophil Extracellular Trap Formation in Antineutrophil Cytoplasmic Antibody–Associated Vasculitis Compared to Systemic Lupus Erythematosus
Author(s) -
Dam Laura S.,
Kraaij Tineke,
Kamerling Sylvia W. A.,
Bakker Jaap A.,
Scherer Uli H.,
Rabelink Ton J.,
Kooten Cees,
Teng Y. K. Onno
Publication year - 2019
Publication title -
arthritis and rheumatology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 4.106
H-Index - 314
eISSN - 2326-5205
pISSN - 2326-5191
DOI - 10.1002/art.41047
Subject(s) - neutrophil extracellular traps , autoantibody , immunology , lytic cycle , vasculitis , immune complex , medicine , immune system , pathophysiology , autoimmune disease , antibody , systemic lupus erythematosus , inflammation , disease , virus
Objective Different studies have demonstrated that neutrophil extracellular traps ( NET s) may be involved in the pathophysiology of both antineutrophil cytoplasmic antibody ( 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 NET s. This study aimed to examine whether the mechanisms of NET formation and the composition of NET s are distinct between AAV and SLE . Methods To investigate this hypothesis, healthy neutrophils were stimulated with serum from patients with AAV (n = 80) and patients with SLE (n = 59), and the mechanisms of NET formation and NET composition were compared. Results Both patients with AAV and patients with SLE had excessive NET formation, which correlated with the extent of disease activity (in AAV r = 0.5, P < 0.0001; in SLE r = 0.35, P < 0.01). Lytic NET formation over several hours was observed in patients with AAV , as compared to rapid (within minutes), non‐lytic NET formation coinciding with clustering of neutrophils in patients with SLE . AAV ‐induced NET formation was triggered independent of IgG ANCA s, whereas SLE immune complexes ( IC x) induced NET formation through Fcγ receptor signaling. AAV ‐induced NET formation was dependent on reactive oxygen species and peptidyl arginine deaminases, and AAV ‐induced NET s were enriched for citrullinated histones (mean ± SEM 23 ± 2%). In contrast, SLE ‐induced NET s had immunogenic properties, including binding with high mobility group box chromosomal protein 1 (mean ± SEM 30 ± 3%) and enrichment for oxidized mitochondrial DNA , and were involved in IC x formation. Conclusion The morphologic features, 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 pathophysiologic role of NET s in these different autoimmune diseases.