Neutrophil Extracellular Traps in ANCA-Associated Vasculitis

Abstract

A group of pauci-immune vasculitides, characterized by neutrophil-rich necrotizing inflammation of small vessels and the presence of antineutrophil cytoplasmic antibodies (ANCAs), is referred to as ANCA-associated vasculitis (AAV). ANCAs against proteinase 3 (PR3) (PR3-ANCA) or myeloperoxidase (MPO) (MPO-ANCA) are found in over 90% of patients with active disease, and these ANCAs are implicated in the pathogenesis of AAV. Dying neutrophils surrounding the walls of small vessels are a histological hallmark of AAV. Traditionally, it has been assumed that these neutrophils die by necrosis, but neutrophil extracellular traps (NETs) have recently been visualized at the sites of vasculitic lesions. AAV patients also possess elevated levels of NETs in the circulation. ANCAs are capable of inducing NETosis in neutrophils, and their potential to do so has been shown to be affinity dependent and to correlate with disease activity. Neutrophils from AAV patients are also more prone to release NETs spontaneously than neutrophils from healthy blood donors. NETs contain proinflammatory proteins and are thought to contribute to vessel inflammation directly by damaging endothelial cells and by activating the complement system and indirectly by acting as a link between the innate and adaptive immune system through the generation of PR3- and MPO-ANCA. Injection of NET-loaded myeloid dendritic cells into mice results in circulating PR3- and MPO-ANCA and the development of AAV-like disease. NETs have also been shown to be essential in a rodent model of drug-induced vasculitis. NETs induced by propylthiouracil could not be degraded by DNaseI, implying that disordered NETs might be important for the generation of ANCAs. NET degradation was also highlighted in another study showing that AAV patients have reduced DNaseI activity resulting in less NET degradation. With this in mind, it might be that prolonged exposure to proteins in the NETs due to the overproduction of NETs and/or reduced clearance of NETs is important in AAV. However, not all ANCAs are pathogenic and some might possibly also aid in the clearance of NETs. A dual role for ANCAs in relation to circulating NET levels has been proposed because a negative correlation was observed between PR3-ANCA and NET remnants in patients in remission.

ANCA Glomerulonephritis and Vasculitis

“…Both MPO-ANCA and PR3-ANCA IgG can activate primed normal human neutrophils in vitro causing respiratory burst with release of toxic oxygen radicals, degranulation with release of lytic and proinflammatory enzymes, release of complement alternative pathway-activating factors, and release of neutrophil extracellular traps (NETS), which contain extruded DNA with adherent cytoplasmic proteins that can cause tissue injury and augment the autoimmune response (19,23,24). Priming of neutrophils, for example by cytokines, is required for optimum activation by ANCA IgG.…”

“…Neutrophils are activated when ANCA IgG bound to ANCA antigens engages Fc g receptors on the surface of neutrophils. ANCA-activated neutrophils adhere to endothelial cells and release mediators of inflammation and cell injury, including NETS (19,24) (Figure 4). …”

“…NETosis is a form of neutrophil activation and cell death that results in the release of NETS that contain a framework of extruded DNA from decondensed chromatin decorated with multiple adherent cytoplasmic proteins, including MPO and PR3, many of which have antimicrobial properties. NETosis could contribute to the pathogenies of ANCA disease, both by presenting PR3 and MPO proteins to the immune system in a way that facilitates the autoimmune ANCA response, and by mediating inflammatory injury at sites of ANCA-induced activation through destructive enzymes and complement-activating factors (24).…”

Macrophage Extracellular Traps: A Scoping Review

“…ETs have been implicated in diverse disease states ranging from conditions of aseptic inflammation, such as gout, to vascular disorders including preeclampsia and thrombosis [13][14][15][16]. Inadequate resolution and degradation of these structures is also a topic of recent research; prolonged exposure of self-antigens comprising ETs can result in autoimmune diseases including systemic lupus erythematosus (SLE) and antineutrophil cytoplasmic autoantibodies (ANCA)-associated vasculitis [17,18].…”

The Contribution of Innate Immunity to the Pathogenesis of ANCA-associated Vasculitis

“…In line with our results, NET-associated components such as NE, calprotectin, HMGB1 and MPO have also been shown to be elevated in the circulation of AAV patients compared with HC, and some of them have also bene elevated during active disease compared with remission (Soderberg and Segelmark 2016). Although infections can induce NET formation, we could not find a correlation with CRP in patients with active disease, suggesting that infections and NET formation in these patients to some extent represent separate or partly overlapping pathogenic routes.…”