Neutrophils from vasculitis patients exhibit an increased propensity for activation by anti-neutrophil cytoplasmic antibodies

Abstract

SummaryAnti-neutrophil cytoplasmic antibodies (ANCA) are thought to be pathogenic in ANCA-associated vasculitis (AAV) by stimulating polymorphonuclear leucocytes (PMNs) to degranulate and produce reactive oxygen species (ROS). The aim of this study was to investigate if PMNs from AAV patients are stimulated more readily by ANCA compared with PMNs from healthy controls (HCs). Differences in ANCA characteristics that can account for different stimulation potential were also studied. PMNs from five AAV patients and five HCs were stimulated with 10 different immunoglobulins (Ig)Gs, purified from PR3-ANCA-positive patients, and ROS production, degranulation and neutrophil extracellular trap (NET) formation was measured. ANCA levels, affinity and clinical data of the AAV donors were recorded. The results show that PMNs from AAV patients produce more intracellular ROS (P = 0·019), but degranulate to a similar extent as PMNs from HCs. ROS production correlated with NET formation. Factors that may influence the ability of ANCA to activate PMNs include affinity and specificity for N-terminal epitopes. In conclusion, our results indicate that PMNs from AAV patients in remission behave quite similarly to HC PMNs, with the exception of a greater intracellular ROS production. This could contribute to more extensive NET formation and thus an increased exposure of the ANCA autoantigens to the immune system.

Circulating mitochondrial DNA in serum of patients with granulomatosis with polyangiitis

“…Ohlsson et al . reported that neutrophils in patients with ANCA‐associated vasculitis exhibited an increased propensity for activation by cANCAs . Studies by Pankhurst et al .…”

“…ANCA-mediated neutrophil activation seems to involve both Fc and Fab fragments of the antibody, but the exact mechanism of this process is not completely understood [2][3][4]. Ohlsson et al reported that neutrophils in patients with ANCA-associated vasculitis exhibited an increased propensity for activation by cANCAs [5]. Studies by Pankhurst et al showed that different immunoglobulin G subclasses of ANCA had different abilities for neutrophil activation [6].…”

IgA- and SIgA anti-PR3 antibodies in serumversusorgan involvement and disease activity in PR3-ANCA-associated vasculitis

“…Immunoglobulin (Ig)G-class PR3-ANCA as well as MPO-ANCA can bind their target antigens exposed on the neutrophil surface (for instance, after cytokine-priming), resulting in cross-linking of Fc-receptors, complement activation and neutrophil oxidative burst [3,[11][12][13][14][15][16][17][18]. ANCA of different isotypes have been described previously, including IgG, IgA and IgM-ANCA, where IgG-ANCA is the predominating circulating isotype in AAV, and is monitored frequently in GPA as a means to assess disease activity [19][20][21], although the clinical utility remains controversial [22][23][24].…”

Necroptosis controls NET generation and mediates complement activation, endothelial damage, and autoimmune vasculitis

“…NETs are lattice-like structures containing DNA, histones, and neutrophil granule proteins, including the ANCA antigens MPO and PR3 (12,17,18). ANCA-stimulated neutrophils were shown to release NETs in vitro, and circulating as well as glomerular deposited NETs were detected in AAV patients (12,(19)(20)(21). It was suggested that NETs are immunogenic and participate in the tolerance breakdown toward the ANCA autoantigens (12,22,23).…”