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Originally published online as doi:10.1189/jlb.1202611 on May 22, 2003

Published online before print May 22, 2003
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(Journal of Leukocyte Biology. 2003;74:3-15.)
© 2003 by Society for Leukocyte Biology

Neutrophil-activating potential of antineutrophil cytoplasm autoantibodies

Agnieszka A. Rarok, Pieter C. Limburg and Cees G. M. Kallenberg

Department of Internal Medicine, University Hospital Groningen, The Netherlands

Correspondence: Prof. Dr. C. G. M. Kallenberg, Department of Internal Medicine, University Hospital Groningen, Hanzeplein 1, 9713 GZ Groningen, The Netherlands. E-mail: c.g.m.kallenberg{at}int.azg.nl


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ABSTRACT
 
Accumulating in vivo and in vitro evidence supports the hypothesis that antineutrophil cytoplasm autoantibodies (ANCA) with specificity for proteinase 3 (PR3) and myeloperoxidase (MPO) are involved in the pathophysiology of small-vessel vasculitis. The best-described effector function of these autoantibodies is stimulation of neutrophils to produce reactive oxygen species and to release proteolytic enzymes. Neutrophil activation requires interaction of monomeric ANCA with PR3/MPO and Fc{gamma} receptors, but also other mechanisms—for instance, stimulation by ANCA-containing immune complexes—cannot be excluded. This review focuses on the mechanisms of neutrophil activation by ANCA. We discuss the molecules involved in ANCA binding to the neutrophil surface and in triggering the functional responses. We summarize current knowledge on the signal-transduction pathways initiated by ANCA and on the factors determining susceptibility of neutrophils to activation by these autoantibodies.

Key Words: ANCA • proteinase 3 • myeloperoxidase • Fc{gamma} receptors • oxidative burst


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INTRODUCTION
 
Antineutrophil cytoplasm autoantibody (ANCA)-associated small-vessel vasculitis is a systemic disease of unknown etiology, characterized by chronic inflammation of blood vessels. It may affect people of all ages but is most common in older adults, usually in their 50s and 60s [1 ]. The incidence of ANCA-associated vasculitis, currently estimated as more than 20 per million, is increasing [2 ].

Since 1990, ANCA with specificity for two different neutrophil enzymes, proteinase 3 (PR3-ANCA) and myeloperoxidase (MPO-ANCA), have been suggested to contribute to the pathogenesis of small-vessel vasculitis [3 4 5 6 7 ]. These autoantibodies have been found to stimulate neutrophils to adhere to cytokine-activated endothelial cells [8 ], generate reactive oxygen species (ROS) [9 , 10 ], release proteolytic enzymes from the intracellular stores [9 ], and secrete proinflammatory cytokines [11 ]. Eventually, all these effects may result in damage of endothelial cells and lead to vasculitis.

This review will focus on the mechanisms of neutrophil activation by ANCA. We will discuss the molecules involved in ANCA binding to the neutrophil surface and triggering the functional responses. In particular, factors determining the susceptibility of neutrophils to activation by ANCA will be addressed.


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ANCA-ASSOCIATED SMALL-VESSEL VASCULITIDES
 
ANCA-associated small-vessel vasculitis is the most common, primary, systemic, small-vessel vasculitis in adults. It affects arterioles, venules, and capillaries but may also involve arteries and veins [1 ]. ANCA-associated small-vessel vasculitis includes three major categories, defined by the Chapel Hill International Consensus Conference [12 ]: Wegener’s granulomatosis (WG), microscopic polyangiitis (MPA), and Churg-Strauss syndrome (CSS). These diseases share a common pathology with focal necrotizing lesions of blood vessels, which affect many different vessels and organs. WG is characterized by granulomatous inflammation of the upper and/or lower respiratory tract combined with necrotizing pauci-immune glomerulonephritis in ~80% of WG patients. Although PR3-ANCA are found in the majority of patients with WG, they are often absent from patients with a limited form of this disease, even in its active phase. Moreover, a small subset of patients remains persistently ANCA-negative. MPA is characterized by pauci-immune, necrotizing, small-vessel vasculitis without evidence of granulomatous inflammation. Approximately 90% of patients with MPA have glomerulonephritis accompanied by a variety of other organ involvement. In CSS, the vasculitic phase is preceded by asthma and eosinophilic-infiltrative disease. Compared with WG and MPA, patients with CSS less frequently suffer from renal disease but more frequently from neuropathy and cardiac disease.


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ANTINEUTROPHIL CYTOPLASM AUTOANTIBODIES
 
One of the characteristic features of the aforementioned vasculitides is the presence of ANCA, specific for PR3 or MPO. ANCA are routinely detected in serum of patients by indirect immunofluorescence on ethanol-fixed neutrophils [13 14 15 ]. Using this technique, at least three different fluorescence patterns can be distinguished: a cytoplasmic pattern, strongly associated with antibodies to PR3 [16 ]; a perinuclear pattern, associated with antibodies to MPO [17 ] or to several other enzymes including lactoferrin [18 ], elastase [19 ], and cathepsin G [20 ]; and an atypical pattern.

PR3-ANCA are characteristic for patients suffering from WG [13 , 16 , 21 22 23 ]. However, they can also be detected in patients with MPA and in a minority of patients with idiopathic-necrotizing crescentic glomerulonephritis (NCGN), a renal, limited form of MPA [24 ]. MPO-ANCA have been first described in patients with NCGN [17 ], but they are also present in the majority of patients with MPA and in 70% of patients with CSS [25 , 26 ]. MPO-ANCA are also detected in 5–20% of patients with WG and in sera of patients with other inflammatory disorders [24 , 25 , 27 ].

ANCA of specificities other than PR3 or MPO have been described in many other nonvasculitic inflammatory disorders, such as chronic inflammatory bowel disease [28 ] and rheumatoid arthritis [29 ]. Most striking is the prevalence of ANCA specific for bactericidal/permeability-increasing protein in patients with cystic fibrosis [30 , 31 ]. The role of these autoantibodies in the pathophysiology of the associated diseases has not been established yet.


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EVIDENCE FOR A PATHOPHYSIOLOGICAL ROLE OF ANCA IN SYSTEMIC VASCULITIS
 
Several clinical observations suggest that PR3- and MPO-ANCA play an important role in the pathophysiology of vasculitis. First, increase in ANCA titer frequently precedes a relapse [21 , 32 33 34 ], and decline in titer (or even complete disappearance) is observed when remission is induced [21 ]. Furthermore, patients who are persistently PR3-ANCA-positive during remission are at high risk to develop relapses [35 , 36 ]. Finally, the development of relapses in WG can be successfully prevented by treatment based on changes in ANCA [37 , 38 ]. It is interesting that some patients with quiescent disease have very high ANCA titers [39 ], and conversely, in some patients, active disease is not associated with the presence of ANCA, suggesting that ANCA-independent mechanisms can also lead to vasculitis in these diseases.

The results of studies in experimental animals [40 41 42 ] further support the hypothesis that ANCA are involved in damage observed in patients suffering from ANCA-associated vasculitides. In the recent study by Xiao et al. [42 ], transfer of splenocytes from MPO-deficient mice immunized with MPO to Rag2 knockout mice, which lack functioning B and T lymphocytes, led to the development of severe necrotizing and crescentic glomerulonephritis and systemic necrotizing vasculitis. Also, direct intravenous injection of anti-MPO antibodies into wild-type or Rag2 knockout mice resulted in focal necrotizing and crescentic glomerulonephritis, which provides strong evidence for the pathogenic properties of MPO-ANCA. In the earlier study by Heeringa et al. [40 ], rats immunized with MPO and subsequently challenged with a subnephritogenic dose of antiglomerular basement membrane (GBM) antibodies developed severe necrotizing and crescentic glomerulonephritis, whereas rats injected with anti-GBM antibodies developed only mild glomerulonephritis.

In vitro experimental studies shed more light on the mechanisms by which ANCA can exert their phlogistic potential. Most of the studies focus on interactions of ANCA with neutrophils and monocytes, as these cells are the main source of ANCA antigens, and their activation in systemic vasculitis has been demonstrated in vivo [43 ]. In the next part of this review, we will discuss current knowledge regarding the mechanisms of neutrophil activation by ANCA.


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ANCA ANTIGENS: PROPERTIES AND DISTRIBUTION
 
MPO is a highly glycosylated, heme-containing enzyme present in the azurophilic granules of neutrophils [44 ] and is involved in the production of hypochloric acid from hydrogen peroxide and chloride ions [45 ]. Hypochloric acid and its metabolites are effective in killing phagocytosed bacteria and viruses [45 ] and by inactivating proteinase inhibitors, play an indirect role in tissue degradation in inflammatory disorders [46 ]. Except from being present in azurophilic granules of neutrophils, MPO is expressed on the surface of human monocytes and to a lesser extent, on the surface of neutrophils [9 , 47 ].

PR3 is a serine proteinase originally found in cells of the granulocytic and monocytic lineage [48 49 50 51 52 53 54 55 ]. First, mRNA of PR3 was shown in early phases of neutrophil/monocyte development only [50 , 52 , 54 , 55 ]. Recently, however, it has been demonstrated that transcription of the PR3 gene in mature neutrophils and peripheral mononuclear cells is also possible and can be induced by tumor necrosis factor {alpha} (TNF-{alpha}) [56 ] and interferon-{gamma} [57 ].

Several investigators reported the presence of PR3 in nonmyeloid cells also [58 59 60 61 ], but this controversial observation is still a matter of debate. Mayet et al. [59 ] described expression of PR3 in a number of nonmyeloid cells, including endothelial cells, and demonstrated expression of PR3 on the endothelial cell surface upon stimulation with proinflammatory cytokines. Although some investigators have confirmed these results [58 , 60 ], others were not able to demonstrate the presence of endogenous PR3 in endothelial cells [62 63 64 ]. There is increasing evidence that PR3 can bind to the endothelial cell surface. As suggested by Taekema-Roelvink et al. [65 ], exogenous, possibly neutrophil-derived, PR3 may interact with the surface of endothelial cells via a PR3-specific receptor, which has not been fully characterized yet. It is interesting that PR3 has also been found in lung tissue, which is another site frequently inflamed in WG. In the study by Brockmann et al. [61 ], PR3 localized in parenchymal cells of lung tissue of healthy inividuals and WG patients and was significantly up-regulated in WG patients, as compared with healthy individuals. Nevertheless, the neutrophil is still considered to be the major source of PR3 in humans.


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SUBCELLULAR LOCALIZATION OF PR3 AND MPO
 
Compartmentalization of an autoantigen in the cell determines its accessibility for interaction with autoantibodies, which may lead to functional responses. For this reason, in the past few years, several investigators analyzed subcellular localization of ANCA antigens in the neutrophil and its consequences (Table 1 ). The presence of MPO is restricted to the azurophilic granules and the cell membrane only [9 , 47 , 70 ], whereas subcellular distribution of PR3 is more complicated. Originally, PR3 was found to be stored in azurophil granules of the neutrophil [48 , 49 , 55 ]. A recent study using immunoelectron microscopy showed, however, that PR3 also localizes in specific granules and secretory vesicles of the neutrophil [67 ]. Even more interesting, PR3 can also be present on the surface of resting neutrophils and unlike MPO, be expressed on the total cell population or on a subset of neutrophils [67 68 69 , 86 ] (Fig. 1 ). Neutrophils express only a small amount of PR3 on their membrane, estimated to be ~0.1% of PR3 stored intracellularly (unpublished observation). The presence of mPR3- and mPR3+ cells within one individual, designated as the bimodal mPR3 expression, has been suggested to be genetically determined [68 , 87 ]. Several observations support this hypothesis. First, as shown by flow cytometric analysis of mPR3 expression on purified blood neutrophils on two different occasions, the percentages of mPR3- and mPR3+ cells are stable in time [68 , 69 , 87 ]. Second, studies in families suggested that the mPR3 expression phenotype is determined by two codominant alleles [68 ] and also showed that monozygotic twins display the same mPR3 expression pattern on their neutrophils [87 ]. Whether mPR3- and mPR3+ neutrophils contain the same amount of intracellular PR3 is not clear yet. The number of mPR3+ neutrophils and the level of PR3 expression on the surface of resting neutrophils have been shown to be increased in WG patients in remission, as compared with healthy controls [68 , 69 ]. It is interesting that the level of mPR3 expression correlates with the incidence and rate of relapse of WG, suggesting that PR3 expressed on the neutrophil surface is a risk factor for recurrent, active disease [69 ]. Hypothetically, PR3 present on the surface of resting neutrophils may function as the specific attachment site for ANCA, which might have consequences for the initiation of ANCA-induced neutrophil activation.


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  		Table 1. Subcellular Localization of Selected Proteins Involved in Neutrophil Activation



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  		Figure 1. Patterns of PR3 expression on the surface of resting neutrophils as analyzed by flow cytometry. The bold line represents staining with monoclonal anti-PR3 antibody; the thin line is nonspecific binding of an isotype-matched control antibody (reprinted with permission from Rarok et al. [69 ]). mPR3-/+, Membrane PR3-negative/positive, respectively; PE, phycoerythrin fluorescence intensity (PR3 expression level).

The molecular mechanism of the expression of PR3 on the membrane of resting neutrophils is still unclear. PR3 is not a transmembrane protein and does not seem to be attached to the cell surface via charge interactions nor via a glycosylphosphatidylinositol (GPI) anchor [67 ]. It might, however, interact with lipid structures of the neutrophil membrane [88 ], with a membrane protein, or even with a PR3-specific receptor, as has been described in endothelial cells [65 ].

The level of PR3 expression on the neutrophil surface may change between different stages of the disease [47 ], but the proportion of mPR3+ neutrophils remains unchanged [68 ]. As shown by Muller Kobold et al. [47 ], neutrophils of patients in an active phase of WG express more PR3 than during quiescent disease, and the level of mPR3 expression correlates with disease severity. This transient up-regulation of PR3 on the neutrophil surface is possibly a result of degranulation of intracellular stores of PR3—secretory vesicles or specific granules—and (re)binding of PR3 to the neutrophil surface in inflammatory conditions [67 ]. It is interesting that other neutrophil granule enzymes, including the PR3 homologue neutrophil elastase (HLE), are not up-regulated on the neutrophil surface upon degranulation but are released in the extracellular milieu [67 ].


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NEUTROPHIL PRIMING BY TNF-{alpha}
 
The aim of priming is to prepare the neutrophil for the appropriate response to a subsequent stimulus. This state of neutrophil preactivation can be induced by low concentrations of various proinflammatory cytokines released during infection or tissue damage (reviewed in ref. [89 ]), such as TNF-{alpha} [90 91 92 93 ], granulocyte macrophage-colony stimulating factor [94 ], and transforming growth factor-ß1 [95 ]. Increased levels of TNF-{alpha} have been reported in systemic vasculitis [96 , 97 ], suggesting its involvement in the pathophysiology of this disorder. Indeed, neutrophil priming with TNF-{alpha} in vitro has been shown to be required for the ANCA-induced respiratory burst [9 , 90 ].

One of the most important TNF-{alpha}-induced processes facilitating neutrophil activation is degranulation of secretory vesicles and specific granules [98 , 99 ] and their fusion with the plasma membrane leading to up-regulation of cell-surface expression of many molecules (Table 2 ), including the ANCA antigens, PR3 and MPO [9 , 90 , 91 , 104 ], adhesion molecules such as ß2 integrins [76 77 78 ], and fMLP receptors [102 , 103 ]. Moreover, TNF-{alpha}-induced degranulation plays an important role in NADPH oxidase complex formation, as it results in translocation of cytochrome b558 to the cell surface [82 ].


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  		Table 2. Effects of Priming Concentrations of TNF-{alpha} on the Neutrophil

In vitro, TNF-{alpha} at priming concentrations has been shown to cause two- to threefold up-regulation of PR3 expression on the neutrophil surface [90 91 92 93 ] (Table 2) . In neutrophils displaying a bimodal PR3 expression pattern, TNF-{alpha} seems to have a comparable effect on mPR3- and mPR3+ subsets and does not change the proportion of these subsets in the total neutrophil population (unpublished observations). Compared with the effect on PR3 expression, the effect of TNF-{alpha} on the level of MPO on the neutrophil surface is less pronounced [9 , 90 91 92 ]. The reason for this difference in sensitivity to up-regulation by TNF-{alpha} might be a difference in the intracellular localization of PR3 and MPO, where MPO localizes only in azurophil granules [70 ], which require a strong stimulus to degranulate [105 ], whereas PR3 is also present in the easily mobilizable-specific granules and secretory vesicles [67 ]. Moreover, in contrast to PR3, MPO does not display a bimodal expression pattern.

Except for inducing the up-regulation of certain molecules on the neutrophil surface, TNF-{alpha} can cause lateral changes in the receptor distribution in the cell membrane. Very recently, Reumaux et al. [100 , 101 ], using confocal scanning microscopy, demonstrated TNF-{alpha}-induced clustering of ß2 integrins and Fc{gamma}RIIa, suggesting cooperation of these receptors in triggering neutrophil activation.


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INVOLVEMENT OF Fc{gamma}Rs IN NEUTROPHIL ACTIVATION BY ANCA
 
At present (despite some controversy discussed further), the general assumption is that neutrophil activation by ANCA requires direct recognition of PR3 or MPO via the Fab region of the antibody and interaction of the Fc part of the antibody with Fc{gamma}Rs on the neutrophil surface. Neutrophils predominantly express Fc{gamma}RIIa (CD32) and Fc{gamma}RIIIb (CD16), which differ in their ability to bind monomeric or complexed IgG and in their affinity for different subclasses of IgG [106 , 107 ].

Fc{gamma}RIIa is a transmembrane protein with a tyrosine-based activation domain (immunoreceptor tyrosine-based activation motif) in its cytoplasmic domain [108 ]. Affinity for different IgG subclasses by Fc{gamma}RIIa is influenced by R/H (arg/his) polymorphism at amino acid position 131 [109 ]. The Fc{gamma}RIIa–R/R131 genotype, in combination with the Fc{gamma}RIIIa–F/F158 genotype of monocytes, has been found to be associated with an increased relapse rate in WG [110 ]. Fc{gamma}RIIa is the only Fc{gamma}R that interacts with monomeric IgG2. Moreover, it is characterized by a high affinity for the IgG3 subclass [106 ], which is over-represented during active disease in patients with ANCA-associated vasculitis [111 ] and associated with renal involvement [112 ]. Consistent with these in vivo observations, in vitro experiments also underscore the involvement of Fc{gamma}RIIa in triggering the neutrophil oxidative burst, as blocking this receptor with a specific monoclonal antibody (mAb) abrogates oxygen radical release in response to stimulation with ANCA [90 , 92 , 113 ]. However, incubation of neutrophils with anti-Fc{gamma}RIIa antibody before stimulation with ANCA usually causes only a partial blocking of the oxidative burst [113 , 114 ], suggesting that some other mechanism may be involved as well. As measurement of neutrophil activation is commonly studied by analysis of the oxidative burst, there is still not much known about the role of Fc{gamma}RIIa in the very early ANCA-induced responses of neutrophils, such as cytoskeletal changes.

Another receptor possibly involved in neutrophil activation by ANCA, Fc{gamma}RIIIb, is a GPI-anchored protein, expressed on neutrophils at tenfold higher density than Fc{gamma}RIIa [115 ]. Although the NA1 allele of Fc{gamma}RIIIb [109 ] has been shown to be a risk factor for the development of renal disease in patients with WG [116 ], in vitro elucidation of the involvement of this receptor in neutrophil activation by ANCA is difficult as a result of its transient expression on the cell surface (shedding on activation) [73 , 117 , 118 ]. Using an inhibitor of Fc{gamma}RIIIb shedding, Kocher et al. [119 ] demonstrated that PR3- and MPO-ANCA, as well as corresponding mAb, can interact with Fc{gamma}RIIIb. They suggested that Fc{gamma}RIIIb may be preferentially engaged when the ANCA target, that is, PR3 or MPO, is limiting and that it is responsible for triggering neutrophil responses in the initial phase of activation. Indeed, binding PR3-ANCA to neutrophils induces a transient, proadhesive phenotype characterized by an increased expression of CD11b and preserved expression of CD62L [119 , 120 ]. The role of Fc{gamma}RIIIb in late, functional responses of neutrophils is still not very clear. Blocking Fc{gamma}RIIIb has no or very little effect on the ANCA-induced respiratory burst of neutrophils measured 25–60 min after stimulation [90 , 101 ]. Moreover, Fc{gamma}RIIIb-deficient neutrophils are capable of mounting a normal oxidative response to anti-PR3 and anti-MPO mAb [101 ], which excludes a crucial role of this receptor in the oxidative burst. In contrast to the above-mentioned results, in a study by Ben-Smith et al. [121 ], anti-Fc{gamma}RIIIb antibody reduced PR3-ANCA- or MPO-ANCA-induced superoxide production by 15–61%, as measured 15 min after stimulation.

The mechanism by which Fc{gamma}RIIIb may be involved in ANCA-induced neutrophil activation is still unclear. Although for a long time, GPI-anchored proteins had been thought not to be able to transduce signals as a result of their lack of a transmembrane domain, it turned out that Fc{gamma}RIIIb is capable of inducing a rise in the intracellular-free calcium concentration [Ca2+]i [122 123 124 125 ], actin polymerization [126 ], and respiratory burst [127 ]. This observation raises the hypothesis that Fc{gamma}RIIIb might use signal-transduction pathways of other (associated) molecules.


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MORE THAN A SIMPLE CROSS-LINKING OF AUTOANTIGEN AND Fc{gamma}R?
 
It cannot be excluded that molecules other than Fc{gamma}Rs are involved in neutrophil activation by ANCA. Kettritz at al. [114 ] demonstrated that not only intact ANCA molecules but also their F(ab')2 fragments are capable of inducing oxygen radical production by primed neutrophils. This observation cannot be explained simply by stimulation of the cell via PR3 or MPO molecules, as these proteins do not possess a transmembrane domain [128 ] and therefore are not able to trigger the signaling cascade leading to neutrophil activation directly. Possibly, ANCA antigens are associated with another, yet not identified, membrane protein. For instance, PR3 or MPO has been suggested to interact with ß2integrins, particularly CD11b/CD18 [129 , 130 ], which are capable of outside-in signaling [131 ]. This is interesting, especially in the context of recent findings of Reumaux et al. [90 ], who showed that blocking ß2 integrins with an anti-CD18 mAb abolishes the ANCA-induced respiratory burst and that ß2 integrin-deficient neutrophils from patients with leukocyte adhesion deficiency-1 cannot become activated by anti-PR3 or anti-MPO mAb [101 ]. They proposed that ligation of ß2integrins, but not necessarily adhesion of the neutrophil, is needed for ANCA-induced neutrophil activation. Moreover, using confocal scanning microscopy, the same authors demonstrated that ß2 integrins and Fc{gamma}RIIa form clusters on the surface of TNF-{alpha}-primed neutrophils [100 , 101 ], which confirmed previous observations by Annenkov et al. [132 ]. Recently, several studies have demonstrated the existence of large, inducible, detergent-resistant complexes in the cell membrane that contain important receptors and signaling molecules including ß2integrins and Fc{gamma}Rs but also many GPI-linked membrane proteins that themselves are not capable of transmitting signals [125 , 133 134 135 136 ]. Spatial interactions between molecules within such clusters may result in cooperation in neutrophil activation. As mentioned above, despite the absence of a transmembrane domain, Fc{gamma}RIIIb is capable of initiating calcium release [123 , 125 ], actin polymerization [126 ], and respiratory burst [127 ] in response to immune complexes. Experiments by Zhou et al. [137 , 138 ] demonstrated that the respiratory burst of neutrophils requires engagement of Fc{gamma}RIIIb and ß2integrins and uses a pathway that involves Fc{gamma}RIIa. These findings were further confirmed with regard to stimulation by ANCA in the above-mentioned study by Reumaux et al. [90 ], which showed that anti-CD18 mAb abolishes oxygen radical production by anti-PR3 and anti-MPO antibodies. ß2integrins have also been reported to form signal-transducing complexes with other proteins such as CD63 [135 , 139 ] and the GPI-anchored urokinase-type plasminogen activator receptor [133 , 140 141 142 ]. Based on these observations, it is conceivable that such TNF-{alpha}-induced clusters may also contain PR3 or MPO, which despite the lack of a signaling domain, might indirectly trigger/enhance neutrophil activation by their association with other proteins.


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SIGNAL-TRANSDUCTION PATHWAYS INVOLVED IN NEUTROPHIL ACTIVATION BY ANCA
 
The interactions between ANCA antigens and proteins clustered on the surface of primed neutrophils would define the signal-transduction pathway(s) triggered by ANCA. Although the routes have not been fully elucidated yet, hypothetically, ANCA may activate neutrophils in several different ways (Fig. 2 ).



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  		Figure 2. Signal-transduction pathways involved in neutrophil activation by ANCA (see text for explanation). (A) Activation by monomeric ANCA, (B) activation by ANCA-containing immune complexes (ICX), (C) hypothetical mechanism of neutrophil activation by monomeric ANCA involving "activation clusters." CYT b558, Cytochrome b558; ERK, extracellular signal-regulated kinase; MAPK, mitogen-activated protein kinase; PI3-K, phosphatidylinositol-3-kinase; PKB, protein kinase B; PKC, protein kinase C; PLD, phospholipase D; PLC, phospholipase C. Unknown or hypothetical pathways are indicated with a question mark.

As the first prerequisite for neutrophil activation by ANCA is the accessibility of PR3/MPO on the cell surface, signaling mechanisms involved in priming by TNF-{alpha} have been studied. TNF-{alpha}-induced translocation of ANCA antigens from cytoplasmic granules to the cell surface is controlled by the p38 MAPK [145 ]. Degranulation of secretory vesicles and specific granules is also responsible for translocation and assembly of NADPH oxidase components [82 ] necessary for the oxidative burst.

According to a generally accepted mechanism, the cross-linking of PR3/MPO and Fc{gamma}RIIa on the surface of primed neutrophils induces the oxidative burst (Fig. 3 ). This process has been shown to involve the p101/p110{gamma} isoform of PI3-K [121 ] and PKB/Akt [121 , 150 ] (Fig. 2A) . Activation of PI3-K is tyrosine kinase-dependent and is paralleled by activation of ERK [145 ]. The relation between ERK and neutrophil activation is currently unknown. Also a tyrosine kinase-independent route, involving PKC but not PLD, has been suggested to lead to the activation of NADPH oxidase [149 ]. PR3-ANCA are also potent inductors of the 5-lipoxygenase (5-LO) pathway in primed neutrophils [153 ]. Activity of 5-LO in the presence of arachidonic acid leads to generation of leukotriene B4, which is a potent chemoattractant recruiting more neutrophils to the inflamed site.



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  		Figure 3. Oxidative burst of TNF-{alpha}-primed neutrophils stimulated with monoclonal anti-PR3 antibody (bold line) as measured by dihydrorhodamine 123 (DHR123) assay. The thin line represents oxygen radical production by neutrophils stimulated with a nonspecific, isotype-matched control antibody.

Apart from direct binding of ANCA to primed neutrophils, the oxidative burst of neutrophils may also be activated by immune complexes containing ANCA and PR3/MPO released upon degranulation (Fig. 2B) . Such immune complexes are known to bind to Fc{gamma}RIIa, but they induce signaling pathways slightly different from those described for monomeric ANCA [121 ]. Cross-linking Fc{gamma}RIIa by immune complexes initiates signal transduction proceeding via another form of PI3-K, namely p85/p110, and may also trigger a PLD-dependent route [121 , 151 ].

Although cross-linking PR3 and Fc{gamma}RIIa by ANCA and ligation of Fc{gamma}RIIa by immune complexes lead to activation of different PI3-K isoforms, the final effect is identical, as both isoforms catalyze the same reaction, namely 3-phosphorylation of phosphatidylinositol 4,5-biphosphate to phosphatidylinositol 3,4,5-triphosphate (PIP3) [121 ]. PIP3 plays an important role in the neutrophil oxidative burst by recruiting serine/threonine kinase Akt/PKB [121 , 150 ]. It is interesting that the kinetics of activation of PKB, a major down-stream target of PI3-K, differs between stimulation by monomeric ANCA and Fc{gamma}R ligation by ANCA-containing immune complexes [121 ]. It is very likely that both signaling routes triggered by monomeric ANCA and by immune complexes overlap at a certain point and that only their initial phase differs. Nevertheless, neutrophil activation by ANCA-containing immune complexes may be of minor importance, as ANCA-associated vasculitis is considered a pauci-immune disease, thus characterized by the absence of significant amounts of immune complexes.

At present, the mechanism by which monomeric ANCA triggers activation of distinct signaling molecules is still unclear, but modification of the response by PR3 or MPO cannot be excluded (Fig. 2C) . As mentioned before, PR3 and MPO, together with Fc{gamma}RIIa, Fc{gamma}RIIIb, ß2integrins, and possibly other molecules, may be part of activation clusters or "rafts" on the cell surface, and the downstream signaling triggered by ANCA may be defined by interactions among these molecules. This hypothetical issue, however, requires further investigation.

In the future, more insight into the mechanism of neutrophil activation and the involved signaling pathways can be provided by the use of the microarray technology. Very recently, Yang et al. [154 ] demonstrated that whole ANCA IgG and ANCA F(ab')2 fragments are able to activate leukocytes. In that study, expression of some genes could be induced by whole ANCA IgG only, expression of other genes was unique to ANCA F(ab')2 fragments, and some genes (for instance, interleukin-8, cyclooxygenase-2, differentiation-inducing factor-2) responded to both.


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NEUTROPHIL SURFACE EXPRESSION OF ANCA ANTIGENS, ANCA SPECIFICITY, AND LEVEL OF NEUTROPHIL ACTIVATION
 
Taking into account the molecules involved, the level of neutrophil activation should, at least, be dependent on ANCA type (PR3- or MPO-ANCA), the level of surface expression of PR3/MPO, and Fc{gamma}R polymorphism (which determines the affinity for IgG subclasses).

Clinical and histologic observations [155 156 157 ] support the first assumption that PR3-ANCA and MPO-ANCA may have different activating properties. It has been shown that renal function generally deteriorates more rapidly and with more active lesions in PR3-ANCA-positive patients than in MPO-ANCA-positive patients [155 , 156 ]. There have been two contradictory in vitro studies comparing the activating potential of PR3-ANCA and MPO-ANCA [93 , 158 ]. Harper et al. [93 ] demonstrated that MPO-ANCA-positive IgG preparations are more potent in inducing a calcium flux, oxidative burst, and MPO release than PR3-ANCA-positive IgG preparations. Although they did not take into account the content of PR3- and MPO-specific antibodies in the IgG preparations used, which might have influenced the results, experiments using mAb confirmed this observation. The differences in the activating potential of PR3- and MPO-ANCA were not a result of differences in the expression of the respective antigens on the neutrophil surface, as the level of PR3 expression is usually much higher than that of MPO. The results of Harper et al. [93 ] were in accordance with the original observation by Falk et al. [9 ] but contradictory to the results of Franssen et al. [158 ], who claimed that PR3-ANCA stimulate a greater superoxide release compared with MPO-ANCA. In the latter study, however, the results might have been biased by the use of a broad range of ANCA titers and a TNF-{alpha} concentration, which is known to cause degranulation of neutrophils leading to the release of MPO.

Whether the susceptibility of neutrophils for ANCA activation depends on the level of PR3/MPO expression on the cell surface has not been fully verified yet. It is conceivable that neutrophils lacking PR3 or MPO should not respond to the respective antibodies. PR3 deficiency is not known, but indeed, some authors have reported that MPO-deficient neutrophils are not capable of raising the oxidative burst in response to stimulation with MPO-ANCA [159 ]. It is interesting that our recent in vitro study demonstrated a correlation between the level of neutrophil membrane PR3 expression and early rearrangement of cytoskeleton measured by the actin polymerization assay but not with the extent of the oxidative burst measured 1 h after stimulation with anti-PR3 antibody (unpublished).

The third important element that may determine susceptibility of neutrophils for activation by ANCA is the Fc{gamma}R. Fc{gamma}RIIa and Fc{gamma}RIIIb display functional polymorphism, but only Fc{gamma}RIIa polymorphism influences affinity for different IgG subclasses [109 ]. Neutrophils homozygous for Fc{gamma}RIIa H/H131 bind IgG3 and IgG2 more avidly compared with neutrophils expressing the R/R131 form of Fc{gamma}RIIa [107 ]. This could have implications for in vivo neutrophil activation in patients with WG during the active phase of the disease, which is characterized by an increased level of the IgG3 subclass of ANCA [160 ].


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THE ROLE OF ADHESION IN NEUTROPHIL ACTIVATION BY ANCA
 
Generally, neutrophils are not activated by monomeric ANCA in the circulation, but they must bind first to the vessel wall and migrate through the endothelial cell layer. TNF-{alpha}-induced adhesion via CD11b/CD18 activation has been shown to be instrumental in provoking neutrophil activation by ANCA. Reumaux et al. [90 ] observed that activation of neutrophils by PR3- or MPO-ANCA is strongly impaired when neutrophil adhesion is prevented by stirring or by addition of a blocking anti-CD18 antibody. Conversely, it has been demonstrated that ANCA can directly induce firm adhesion of rolling neutrophils [161 162 163 ] and migration of neutrophils through the endothelium [163 ]. This adhesion is, at least partially, mediated by CD11b/CD18, which is supported by the observation that ANCA are capable of inducing up-regulation of this ß2integrin on the neutrophil surface [164 ]. The relation between neutrophil adhesion and activation by ANCA-containing immune complexes has not been investigated to date. However, it has been suggested that engagement of Fc{gamma}RIIIb by immune complexes in the circulation may lead to a proadhesive phenotype likely to promote systemic vascular damage [120 ].


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CONSEQUENCES OF NEUTROPHIL ACTIVATION
 
Primed neutrophils that have been activated by ANCA degranulate and release PR3, MPO, and elastase and are capable of inducing endothelial cell lysis [8 , 165 ]. It is possible that these cationic proteins, especially MPO, bind to the endothelium via electrostatic interactions and create binding sites for ANCA [65 , 166 ], which results in antibody-dependent, cellular cytotoxicity. Moreover, PR3 and elastase are known to cause tissue injury by induction of endothelial cell detachment and cytolysis [166 167 168 169 ], effects that are related to the proteolytic activity of these enzymes [170 171 172 ]. PR3 and HLE can also induce apoptosis of endothelial cells [173 174 175 ], and although this process is still unclear, it is suggested to be dependent [173 ] and independent [176 ] of the enzymatic activity of PR3.

Injury caused by MPO released from activated neutrophils is related to its peroxidase activity. Reacting with H2O2 and halide ions, which are the result of the oxidative burst, MPO produces highly ROS [164 ], which take part in endothelial cell detachment [166 ]. Moreover, MPO is involved in the formation of nitric oxide-derived inflammatory oxidants [177 ].

The injury caused by the enzymes released from activated neutrophils may be enhanced by another property of ANCA. PR3-ANCA from patients with WG have been shown to interfere with the proteolytic activity of PR3 and with its binding to {alpha}1-antitrypsin (AT) [178 179 180 181 ], a physiological PR3 inhibitor [172 ]. These effects strongly correlate with disease activity [179 , 180 ], which suggests that changes in the functional characteristics of PR3-ANCA may be related to changes in ANCA epitope specificity during the course of the disease. Indeed, it has been observed that the epitopes on PR3 recognized by PR3-ANCA differ between the moment of diagnosis and the time of relapse (A. A. Rarok et al., submitted). In vivo, a functionally dysregulated balance between PR3 and its inhibitor may allow unlimited proteolytic activity of PR3 and lead to extensive tissue injury. Another study demonstrated differences in MPO-ANCA epitope specificity between samples obtained during various relapses [182 ]. It is also interesting that MPO-ANCA has been shown to interfere with the interaction between MPO and its inhibitor celuroplasmin [183 ], but the relation of this effect to disease activity is not known.

Recently, Rooney et al. [184 ] demonstrated that {alpha}1-AT not only can interfere with the PR3-ANCA binding to PR3 on the surface of primed neutrophils but also can reduce the oxidative burst. This effect is possibly a result of masking PR3 by {alpha}1-AT and therefore interfering with PR3-Fc{gamma}RIIa cross-linking. It is interesting that WG patients who are {alpha}1-AT-deficient or have a dysfunctional {alpha}1-AT phenotype (PiZZ) develop more aggressive vasculitis than do WG patients with the functional {alpha}1-AT phenotype (PiMZ or PiMM) [185 ]. This may be a result of, at least in part, a decreased ability of a functionally reduced {alpha}1-AT level to inhibit activation of neutrophils by ANCA, which may result in more tissue damage.


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ACTIVATION-INDUCED APOPTOSIS OF NEUTROPHILS
 
Eventually, extensive activation of neutrophils leads to apoptosis, and apoptotic cells should be cleared by macrophages in a noninflammatory way. In the study by Harper et al. [186 ], TNF-{alpha}-primed neutrophils activated by ANCA show accelerated apoptosis with delayed externalization of phosphatidylserine as a result of the generation of ROS. As phosphatidylserine is one of the most important molecules involved in the recognition of apoptotic cells by macrophages, clearance of these apoptotic neutrophils is decreased. In vivo, this may result in release of toxic substances from disintegrated neutrophils and endothelial cell injury. In contrast, Moosig et al. [187 ] demonstrated that opsonization of already apoptotic neutrophils by ANCA leads to an enhanced uptake by macrophages, which results in an increased release of TNF-{alpha}, which might further prime neutrophils, leading to perpetuation of priming-dependent neutrophil activation.

Neutrophils that have undergone apoptosis lose their ability to produce ROS in response to ANCA stimulation [104 , 188 ], despite the accessibility of large amounts of ANCA antigens [104 , 188 189 190 ], apparently as a result of failure of signal transduction.


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CONCLUSION
 
Accumulating in vivo and in vitro evidence supports the hypothesis that ANCA with specificity for PR3 and MPO are involved in the pathophysiology of small-vessel vasculitis. The best-described effector function of these antibodies is stimulation of neutrophils to produce ROS and to release proteolytic enzymes. Neutrophil activation requires interaction of monomeric ANCA with PR3/MPO and Fc{gamma}Rs, but also other mechanisms, for instance, stimulation by ANCA-containing immune complexes, cannot be excluded. An interesting effect, which can have important implications for the current hypothesis on neutrophil activation by ANCA, is spatial clustering of Fc{gamma}Rs with other cell-surface molecules. Close cooperation between signaling molecules, possibly additionally modified by interaction with nonsignaling molecules such as ANCA antigens, would define specific signal-transduction pathways triggered by ANCA.

Received December 18, 2002; accepted February 24, 2003.


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