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Originally published online as doi:10.1189/jlb.1202611 on 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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REFERENCES
 
    1
  1. Jennette, J. C., Falk, R. J. (1997) Small-vessel vasculitis N. Engl. J. Med. 337,1512-1523[Free Full Text]
    2. 2
  2. Scott, D. G. I. (2000) Epidemiology of systemic vasculitis, increasing incidence? Clin. Exp. Immunol. 120(Suppl. 1),19-20[CrossRef]
    3. 3
  3. Kallenberg, C. G. M., Brouwer, E., Weening, J. J., Cohen Tervaert, J. W. (1994) Anti-neutrophil cytoplasmic antibodies: current diagnostic and pathophysiological potential Kidney Int. 46,1-15[Medline]
    4. 4
  4. Muller Kobold, A. C., van der Geld, Y. M., Limburg, P. C., Cohen Tervaert, J. W., Kallenberg, C. G. M. (1999) Cellular mechanisms of renal disease: pathophysiology of ANCA-associated glomerulonephritis Nephrol. Dial. Transplant. 14,1366-1375[Abstract/Free Full Text]
    5. 5
  5. Harper, L., Savage, C. O. S. (2000) Pathogenesis of ANCA-associated systemic vasculitis J. Pathol. 190,349-359[CrossRef][Medline]
    6. 6
  6. Kallenberg, C. G. M., Rarok, A. A., Stegeman, C. A., Limburg, P. C. (2002) New insights into the pathogenesis of antineutrophil cytoplasmic autoantibody-associated vasculitis Autoimmunity Rev. 1,61-66
    7. 7
  7. Savage, C. O. S., Harper, L., Holland, M. (2002) New findings in pathogenesis of ANCA-associated vasculitis Curr. Opin. Rheumatol. 14,15-22[CrossRef][Medline]
    8. 8
  8. Ewert, B. H., Jennette, J. C., Falk, R. J. (1992) Anti-myeloperoxidase antibodies stimulate neutrophils to damage human endothelial cells Kidney Int. 41,375-383[Medline]
    9. 9
  9. Falk, R. J., Terrell, R. S., Charles, L. A., Jennette, J. C. (1990) Anti-neutrophil cytoplasmic autoantibodies induce neutrophils to degranulate and produce oxygen radicals in vitro Proc. Natl. Acad. Sci. USA 87,4115-4119[Abstract/Free Full Text]
    10. 10
  10. Charles, L. A., Caldas, M. L. R., Falk, R. J., Terrell, R. S., Jennette, J. C. (1991) Antibodies against granule proteins activate neutrophils in vitro J. Leukoc. Biol. 50,539-546[Abstract]
    11. 11
  11. Brooks, C. J., King, W. J., Radford, D. J., Adu, D., McGrath, M., Savage, C. O. (1999) IL-1 beta production by human polymorphonuclear leucocytes stimulated by anti-neutrophil cytoplasmic autoantibodies: relevance to systemic vasculitis Clin. Exp. Immunol. 106,273-279
    12. 12
  12. Jennette, J. C., Falk, R. J., Andrassy, K., Bacon, P. A., Churg, J., Gross, W. L., Hagen, E. C., Hoffman, G. S., Hunder, G. G., Kallenberg, C. G. M., McCluskey, R. T., Sinico, R. A., Rees, A. J., van Es, L. A., Waldherr, R., Wiik, A. (1994) Nomenclature of systemic vasculitides. Proposal of an international consensus conference Arthritis Rheum. 37,187-192[Medline]
    13. 13
  13. van der Woude, F. J., Rasmussen, N., Lobatto, S., Wiik, A., Permin, H., van Es, L. A., van der Giessen, M., van der Hem, G. K., The, T. H. (1985) Autoantibodies against neutrophils and monocytes: tool for diagnosis and marker of disease activity in Wegener’s granulomatosis Lancet 1,425-429[Medline]
    14. 14
  14. Wiik, A. (1989) Delineation of a standard procedure for indirect immunofluorescence detection of ANCA APMIS 97(Suppl. 6),12-13
    15. 15
  15. van der Giessen, M., Huitema, M. G., Cohen Tervaert, J. W., Kallenberg, C. G. M. (1989) A technical note on the routinely performed ANCA detection APMIS 97(Suppl. 6),37
    16. 16
  16. Lüdemann, J., Utecht, B., Gross, W. L. (1991) Anti-cytoplasmic antibodies in Wegener’s granulomatosis are directed against proteinase 3 Adv. Exp. Med. Biol. 297,141-150[Medline]
    17. 17
  17. Falk, R. J., Jennette, J. C. (1988) Anti-neutrophil cytoplasmic autoantibodies with specificity for myeloperoxidase in patients with systemic vasculitis and idiopathic necrotizing and crescentic glomerulonephritis N. Engl. J. Med. 318,1651-1657[Abstract]
    18. 18
  18. Coremans, I. E. M., Hagen, E. C., Daha, M. R., van der Woude, F. J., van der Voort, E. A. M., Kleyburg–van der Keur, C., Breedveld, F. C. (1992) Anti-lactoferrin antibodies in patients with rheumatoid arthritis are associated with vasculitis Arthritis Rheum. 35,1466-1475[Medline]
    19. 19
  19. Cohen Tervaert, J. W., Mulder, L., Stegeman, C. A., Elema, J., Huitema, M., The, H., Kallenberg, C. G. (1993) Occurence of autoantibodies to human leukocyte elastase in Wegener’s granulomatosis and other inflammatory disorders Ann. Rheum. Dis. 52,115-120[Abstract/Free Full Text]
    20. 20
  20. Halbwachs-Mecarelli, L., Nusbaum, P., Noel, L. H., Reumaux, D., Erlinger, S., Grunfeld, J. P., Lesavre, P. (1992) Antineutrophil cytoplasmic antibodies (ANCA) directed against cathepsin G in ulcerative colitis, Crohn’s disease and primary sclerosing cholangitis Clin. Exp. Immunol. 90,79-84[Medline]
    21. 21
  21. Cohen Tervaert, J. W., van der Woude, F. J., Fauci, A. S., Ambrus, J. L., Velosa, J., Keane, W. F., Meijer, S., van der Giessen, M., van der Hem, G. K., The, T. H., et al (1989) Association between active Wegener’s granulomatosis and anticytoplasmic antibodies Arch. Intern. Med. 149,2461-2465[Abstract/Free Full Text]
    22. 22
  22. Goldschmeding, R., van der Schoot, C. E., ten Bokkel Huinink, D., Hack, C. E., van den Ende, M. E., Kallenberg, C. G., von dem Borne, A. E. (1989) Wegener’s granulomatosis autoantibodies identify a novel diisopropylfluorophosphate-binding protein in the lysosomes of normal human neutrophils J. Clin. Invest. 84,1577-1587
    23. 23
  23. Niles, J. L., McCluskey, R. T., Ahmad, M. F., Arnaout, M. A. (1989) Wegener’s granulomatosis autoantigen is a novel neutrophil serine proteinase Blood 74,1888-1893[Abstract/Free Full Text]
    24. 24
  24. Kallenberg, C. G. M., Mulder, A. H. L., Cohen Tervaert, J. W. (1992) Anti-neutrophil cytoplasmic antibodies: a still growing class of autoantibodies in inflammatory disorders Am. J. Med. 93,675-682[CrossRef][Medline]
    25. 25
  25. Cohen Tervaert, J. W., Limburg, P. C., Elema, J. D., Huitema, M. G., Horst, G., The, T. H., Kallenberg, C. G. (1991) Detection of autoantibodies against myeloid lysosomal enzymes: a useful adjunct to classification of patients with biopsy-proven necrotizing arteritis Am. J. Med. 91,59-66[CrossRef][Medline]
    26. 26
  26. Guillevin, L., Visser, H., Noël, L. H., Pourrat, J., Vernier, I., Gayraud, M., Oksman, M., Lesavre, P. (1993) Antineutrophil cytoplasm antibodies in systemic polyarteritis nodosa with and without hepatitis B virus infection and Churg-Strauss syndrome J. Rheumatol. 20,1345-1349[Medline]
    27. 27
  27. Peter, H. H., Metzger, D., Rump, A., Röther, E. (1993) ANCA in diseases other than systemic vasculitis Clin. Exp. Immunol. 91(Suppl 1),S12-S14
    28. 28
  28. Stoffel, M. P., Csernok, E., Herzberg, C., Johnston, T., Carroll, S. F., Gross, W. L. (1996) Antineutrophil cytoplasmic antibodies (ANCA) directed against bactericidal/permeability increasing protein (BPI): a new seromarker for inflammatory bowel disease and associated disorders Clin. Exp. Immunol. 104,54-59[CrossRef][Medline]
    29. 29
  29. Brimnes, J., Halberg, P., Jacobsen, S., Wiik, A., Heegaard, N. H. (1997) Specificities of anti-neutrophil autoantibodies in patients with rheumatoid arthritis (RA) Clin. Exp. Immunol. 110,250-256[Medline]
    30. 30
  30. Zhao, M. H., Jayne, D. R., Ardiles, L. G., Culley, F., Hodson, M. E., Lockwood, C. M. (1996) Autoantibodies against bactericidal/permeability increasing protein in patients with cystic fibrosis Q. J. Med. 89,259-263
    31. 31
  31. Schulz, H., Weiss, J., Carroll, S. F., Gross, W. L. (2001) The endotoxin-binding bactericidal/permeability-increasing protein (BPI): a target antigen of autoantibodies J. Leukoc. Biol. 69,505-512[Abstract/Free Full Text]
    32. 32
  32. Egner, W., Chapel, H. M. (1990) Titration of antibodies against neutrophil cytoplasmic antigens is useful in monitoring disease activity in systemic vasculitides Clin. Exp. Immunol. 82,244-249[Medline]
    33. 33
  33. Jayne, D. R., Gaskin, G., Pusey, C. D., Lockwood, C. M. (1995) ANCA and predicting relapse in systemic vasculitis QJM 88,127-133
    34. 34
  34. Boomsma, M. M., Stegeman, C. A., van der Leij, M. J., Oost, W., Hermans, J., Kallenberg, C. G. M., Limburg, P. C., Cohen Tervaert, J. W. (2000) Prediction of relapses in Wegener’s granulomatosis by measurement of antineutrophil cytoplasmic antibody levels: a prospective study Arthritis Rheum. 43,2025-2033[CrossRef][Medline]
    35. 35
  35. Gaskin, G., Savage, C. O. S., Ryan, J. J., Jones, S., Rees, A. J., Lockwood, C. M., Pusey, C. D. (1991) Anti-neutrophil cytoplasmic antibodies and disease activity during long-term follow-up of 70 patients with systemic vasculitis Nephrol. Dial. Transplant. 6,689-694
    36. 36
  36. Stegeman, C. A., Cohen Tervaert, J. W., Sluiter, W. J., Manson, W. L., de Jong, P. E., Kallenberg, C. G. M. (1994) Association of chronic nasal carriage of Staphylococcus aureus and higher relapse rate in Wegener’s granulomatosis Ann. Intern. Med. 120,12-17[Abstract/Free Full Text]
    37. 37
  37. Cohen Tervaert, J. W., Huitema, M. G., Hene, R. J., Sluiter, W. J., The, T. H., van der Hem, G. K., Kallenberg, C. G. (1990) Prevention of relapses in Wegener’s granulomatosis by treatment based on antineutrophil cytoplasmic antibody titre Lancet 336,709-711[CrossRef][Medline]
    38. 38
  38. Boomsma, M. M., Stegeman, C. A., Kallenberg, C. G. M., Cohen Tervaert, J. W. (2001) Prevention of relapsing disease in anti-neutrophil cytoplasmic antibody-related necrotizing small-vessel vasculitis: the role for autoantibody-guided and anti-bacterial treatment Kallenberg, C. G. M. Cohen Tervaert, J. W. eds. Disease-Modifying Therapy in Vasculitides Birkhäuser Verlag Basel, Switzerland.
    39. 39
  39. Cohen Tervaert, J. W. (1996) The value of serial ANCA testing during follow-up studies in patients with ANCA associated vasculitides. A review J. Nephrol. 9,232-240
    40. 40
  40. Heeringa, P., Brouwer, E., Klok, P. A., Huitema, M. G., van den Born, J., Weening, J. J., Kallenberg, C. G. M. (1996) Autoantibodies to myeloperoxidase aggravate mild anti-glomerular-basement-membrane-mediated glomelurar injury in the rat Am. J. Pathol. 149,1695-1706[Abstract]
    41. 41
  41. Heeringa, P., Brouwer, E., Cohen Tervaert, J. W., Weening, J. J., Kallenberg, C. G. M. (1998) Animal models of anti-neutrophil cytoplasmic antibody associated vasculitis Kidney Int. 53,253-263[CrossRef][Medline]
    42. 42
  42. Xiao, H., Heeringa, P., Hu, P., Liu, Z., Zhao, M., Aratani, Y., Maeda, N., Falk, R. J., Jennette, J. C. (2002) Antineutrophil cytoplasmic autoantibodies specific for myeloperoxidase cause glomerulonephritis and vasculitis in mice J. Clin. Invest. 110,955-963[CrossRef][Medline]
    43. 43
  43. Brouwer, E., Huitema, M. G., Mulder, A. H. L., Heeringa, P., van Goor, H., Cohen Tervaert, J. W., Weening, J. J., Kallenberg, C. G. M. (1994) Neutrophil activation in vitro and in vivo in Wegener’s granulomatosis Kidney Int. 45,1120-1131[Medline]
    44. 44
  44. Bretz, U., Baggiolini, M. (1974) Biochemical and morphological characterization of azurophil and specific granules of human neutrophilic polymorphonuclear leukocytes J. Cell Biol. 63,251-269[Abstract/Free Full Text]
    45. 45
  45. Hampton, M. B., Kettle, A. J., Winterbourn, C. C. (1998) Inside the neutrophil phagosome: oxidants, myeloperoxidase, and bacterial killing Blood 92,3007-3017[Free Full Text]
    46. 46
  46. Weiss, S. J. (1989) Tissue destruction by neutrophils N. Engl. J. Med. 320,365-376[Medline]
    47. 47
  47. Muller Kobold, A. C., Kallenberg, C. G. M., Cohen Tervaert, J. W. (1998) Leucocyte membrane expression of proteinase 3 correlates with disease activity in patients with Wegener’s granulomatosis Br. J. Rheumatol. 37,901-907[Abstract/Free Full Text]
    48. 48
  48. Dewald, B., Rindler–Ludwig, R., Bretz, U., Baggiolini, M. (1975) Subcellular localization and heterogeneity of neutral proteases in neutrophilic polymorphonuclear leukocytes J. Exp. Med. 141,709-723[Abstract]
    49. 49
  49. Gabay, J. E., Heiple, J. M., Cohn, Z. A., Nathan, C. F. (1986) Subcellular location and properties of bactericidal factors from human neutrophils J. Exp. Med. 164,1407-1421[Abstract/Free Full Text]
    50. 50
  50. Bories, D., Raynal, M. C., Solomon, D. H., Darzynkiewicz, Z., Cayre, Y. E. (1989) Down-regulation of a serine proteinase, myeloblastin, causes growth arrest and differentiation of promyelocytic leukemia cells Cell 59,959-968[CrossRef][Medline]
    51. 51
  51. Csernok, E., Lüdemann, J., Gross, W. L., Bainton, D. F. (1990) Ultrastructural localization of proteinase 3, the target antigen of anti-cytoplasmic antibodies circulating in Wegener’s granulomatosis Am. J. Pathol. 137,1113-1120[Abstract]
    52. 52
  52. Labbaye, C., Musette, P., Cayre, Y. E. (1991) Wegener autoantigen and myeloblastin are encoded by a single mRNA Proc. Natl. Acad. Sci. USA 88,9253-9256[Abstract/Free Full Text]
    53. 53
  53. Charles, L. A., Falk, R. J., Jennette, J. C. (1992) Reactivity of anti-neutrophil cytoplasmic auto-antibodies with mononuclear phagocytes J. Leukoc. Biol. 51,65-68[Abstract]
    54. 54
  54. Zimmer, M., Medcalf, R. L., Fink, T. M., Mattmann, C., Lichter, P., Jenne, D. E. (1992) Three human elastase-like genes coordinately expressed in the myelomonocyte lineage are organized as a single genetic locus on 19pter Proc. Natl. Acad. Sci. USA 89,8215-8219[Abstract/Free Full Text]
    55. 55
  55. Cowland, J., Borregaard, N. (1999) The individual regulation of granule protein mRNA levels during neutrophil maturation explains the heterogeneity of neutrophil granules J. Leukoc. Biol. 66,989-995[Abstract]
    56. 56
  56. Zhou, Z., Richard, C., Ménard, H. A. (2000) De novo synthesis of proteinase 3 by cytokine primed circulating human polymorphonuclear neutrophils and mononuclear cells J. Rheumatol. 27,2406-2411[Medline]
    57. 57
  57. Burchert, A., Wölfl, S., Schmidt, M., Brendel, C., Denecke, B., Cai, D., Odyvanova, L., Lahaye, T., Müller, M. C., Berg, T., Gschaidmeier, H., Wittig, B., Hehlmann, R., Hochhaus, A., Neubauer, A. (2003) Interferon-{alpha}, but not the ABL-kinase inhibitor imatinib (STI571), induces expression of myeloblastin and a specific T-cell response in chronic myeloid leukemia Blood 101,259-264[Abstract/Free Full Text]
    58. 58
  58. Sibelius, U., Hattar, K., Schenkel, A., Noll, T., Csernok, E., Gross, W. L., Mayet, W. J., Piper, H. M., Seeger, W., Grimminger, F. (1998) Wegener’s granulomatosis: anti-proteinase 3 antibodies are potent inductors of human endothelial cell signaling and leakage response J. Exp. Med. 187,497-503[Abstract/Free Full Text]
    59. 59
  59. Mayet, W. J., Csernok, E., Szymkowiak, C., Gross, W. L., Meyer zum Buschenfelde, K. H. (1993) Human endothelial cells express proteinase 3, the target antigen of anticytoplasmic antibodies in Wegener’s granulomatosis Blood 82,1221-1229[Abstract/Free Full Text]
    60. 60
  60. De Bandt, M., Meyer, O., Dacosta, L., Elbim, C., Pasquir, C. (1999) Anti-proteinase 3 (PR3) antibodies (C-ANCA) recognize various targets on the human umbilical vein endothelial cell (HUVEC) membrane Clin. Exp. Immunol. 115,362-368[CrossRef][Medline]
    61. 61
  61. Brockmann, H., Schwarting, A., Kriegsmann, J., Petrow, P., Gaumann, A., Müller, K. M., Galle, P. R., Mayet, W. (2002) Proteinase-3 as the major autoantigen of c-ANCA is strongly expressed in lung tissue of patients with Wegener’s granulomatosis Arthritis Res. 4,220-225[CrossRef][Medline]
    62. 62
  62. King, W. J., Adu, D., Daha, M. R., Brooks, C. J., Radford, D. J., Pall, A. A., Savage, C. O. S. (1995) Endothelial cells and renal epithelial cells do not express the Wegener’s autoantigen, proteinase 3 Clin. Exp. Immunol. 102,98-105[Medline]
    63. 63
  63. Pendergraft, W. F., Alcorta, D. A., Segelmark, M., Yang, J. J., Tuttle, R., Jennette, J. C., Falk, R. J., Preston, G. A. (2000) ANCA antigens, proteinase 3 and myeloperoxidase, are not expressed in endothelial cells Kidney Int. 57,1981-1990[CrossRef][Medline]
    64. 64
  64. Taekema-Roelvink, M. E. J., Daha, M. R. (2000) Proteinase 3 is not expressed by but interacts with endothelial cells: relevance for vasculitis Clin. Exp. Immunol. 120(Suppl. 1),3-4
    65. 65
  65. Taekema-Roelvink, M. E. J., van Kooten, C., Heemskerk, E., Schroeijers, W., Daha, M. R. (2000) Proteinase 3 interacts with a 111-kD membrane molecule of human umbilical vein endothelial cells J. Am. Soc. Nephrol. 11,640-648[Abstract/Free Full Text]
    66. 66
  66. Porteu, F., Nathan, C. F. (1992) Mobilizable intracellular pool of p55 (type I) tumor necrosis factor receptors in human neutrophils J. Leukoc. Biol. 52,122-124[Abstract]
    67. 67
  67. Witko-Sarsat, V., Cramer, E. M., Hieblot, C., Guichard, J., Nusbaum, P., Lopez, S., Lesavre, P., Halbwachs-Mecarelli, L. (1999) Presence of proteinase 3 in secretory vesicles: evidence of a novel, highly mobilizable intracellular pool distinct from azurophilic granules Blood 94,2487-2496[Abstract/Free Full Text]
    68. 68
  68. Witko-Sarsat, V., Lesavre, P., Lopez, S., Bessou, G., Hieblot, C., Prum, B., Noel, L. H., Guillevin, L., Ravaud, P., Sermet-Gaudelus, I., Timsit, J., Grunfeld, J. P., Halbwachs-Mecarelli, L. (1999) A large subset of neutrophils expressing membrane proteinase 3 is a risk factor for vasculitis and rheumatoid arthritis J. Am. Soc. Nephrol. 10,1224-1233[Abstract/Free Full Text]
    69. 69
  69. Rarok, A. A., Stegeman, C. A., Limburg, P. C., Kallenberg, C. G. M. (2002) Neutrophil membrane expression of proteinase 3 (PR3) is related to relapse in PR3-ANCA-associated vasculitis J. Am. Soc. Nephrol. 13,2232-2238[Abstract/Free Full Text]
    70. 70
  70. Cramer, E., Pryzwansky, K. B., Villeval, J. C., Testa, U., Breton-Gorius, J. (1985) Ultrastructural localization of lactoferrin and myeloperoxidase in human neutrophils by immunogold Blood 65,423-432[Abstract/Free Full Text]
    71. 71
  71. Ohlsson, K., Ohlsson, I. (1974) The neutral proteases of human granulocytes. Isolation and partial characterization of granulocyte elastase Eur. J. Biochem. 42,519-527[Medline]
    72. 72
  72. Simms, H. H., D’Amico, R. (1995) Subcellular localization of neutrophil opsonic receptors is altered by exogenous reactive oxygen species Cell. Immunol. 166,71-82[CrossRef][Medline]
    73. 73
  73. Tosi, M. F., Zakem, H. (1992) Surface expression of Fc{gamma} receptor III (CD16) on chemoattractant-stimulated neutrophils is determined by both surface shedding and translocation from intracellular storage compartments J. Clin. Invest. 90,462-470
    74. 74
  74. de Haas, M., Kerst, J. M., van der Schoot, C. E., Calafat, J., Hack, C. E., Nuijens, J. H., Roos, D., Vanoers, R. J. H., von dem Borne, A. E. G. K. (1994) Granulocyte colony-stimulating factor administration to healthy volunteers: analysis of the immediate activating effects on circulating neutrophils Blood 84,3885-3894[Abstract/Free Full Text]
    75. 75
  75. Detmers, P. A., Zhou, D., Powell, D., Lichenstein, H., Kelley, M., Pironkova, R. (1995) Endotoxin receptors (CD14) are found with CD16 (Fc gamma RIII) in an intracellular compartment of neutrophils that contains alkaline phosphatase J. Immunol. 155,2085-2095[Abstract]
    76. 76
  76. Kishimoto, T. K., Jutila, M. A., Berg, E. L., Butcher, E. C. (1989) Neutrophil Mac-1 and MEL-14 adhesion proteins inversely regulated by chemotactic factors Science 245,1238-1241[Abstract/Free Full Text]
    77. 77
  77. Condliffe, A. M., Chilvers, E. R., Haslett, C., Dransfield, I. (1996) Priming differentially regulates neutrophil adhesion molecule expression/function Immunology 89,105-111[CrossRef][Medline]
    78. 78
  78. van den Berg, J. M., Weyer, S., Weening, J. J., Roos, D., Kuipers, T. W. (2001) Divergent effects of tumor necrosis factor {alpha} on apoptosis of human neutrophils J. Leukoc. Biol. 69,467-473[Abstract/Free Full Text]
    79. 79
  79. English, D., Gabig, T., McCarthy, L., Stour, E. F., Leemhuis, T., English, E. (1991) Simultaneous mobilization of Mac-1 (CD11b/CD18) and formyl peptide chemoattractant receptors in human neutrophils Blood 80,776-787
    80. 80
  80. Calafat, J., Kuipers, T., Janssen, H., Borregaard, N., Verhoeven, A. J., Roos, D. (1993) Evidence for small intracellular vesicles in human blood phagocytes containing cytochrome b558 and the adhesion molecule CD11b/CD18 Blood 81,3122-3129[Abstract/Free Full Text]
    81. 81
  81. Sengeløv, H., Kjeldsen, L., Diamond, M. S., Springer, T. A., Borregaard, N. (1993) Subcellular localization and dynamics of Mac-1 ({alpha}2ß2) in human neutrophils J. Clin. Invest. 92,1467-1476
    82. 82
  82. Ward, R. A., Nakamura, M., McLeish, K. R. (2000) Priming of the neutrophil respiratory burst involves p38 mitogen-activated protein kinase-dependent exocytosis of flawocytochrome b558-containing granules J. Biol. Chem. 275,36713-36719[Abstract/Free Full Text]
    83. 83
  83. Borregaard, N., Heiple, J. M., Simons, E. R., Clark, R. A. (1983) Subcellular localization of the b-cytochrome component of the human neutrophil microbicidal oxidase: translocation during activation J. Cell Biol. 97,52-61[Abstract/Free Full Text]
    84. 84
  84. Jesaitis, A. J., Buescher, E. S., Harrison, D., Quinn, M. T., Parkos, C. A., Livesey, S., Linner, J. (1990) Ultrastructural localization of cytochrome b in the membranes of resting and phagocytosing human granulocytes J. Clin. Invest. 85,821-835
    85. 85
  85. Sengeløv, H., Nielsen, M. H., Borregaard, N. (1992) Separation of human neutrophil plasma membrane from intracellular vesicles containing alkaline phosphatase and NADPH-oxidase activity by free flow electrophoresis J. Biol. Chem. 267,14912-14917[Abstract/Free Full Text]
    86. 86
  86. Halbwachs-Mecarelli, L., Bessou, G., Lesavre, P., Lopez, S., Witko-Sarsat, V. (1995) Bimodal distribution of proteinase 3 (PR3) surface expression reflects a constitutive heterogeneity in the polymorphonuclear neutrophil pool FEBS Lett. 374,29-33[CrossRef][Medline]
    87. 87
  87. Schreiber, A., Busjahn, A., Luft, F. C., Kettritz, R. (2003) Membrane expression of proteinase 3 is genetically determined J. Am. Soc. Nephrol. 14,68-75[Abstract/Free Full Text]
    88. 88
  88. Goldmann, W. H., Niles, J. L., Arnaout, M. A. (1999) Interaction of purified human proteinase 3 (PR3) with reconstituted lipid bilayers Eur. J. Biochem. 261,155-162[Medline]
    89. 89
  89. Swain, S. D., Rohn, T. T., Quinn, M. T. (2002) Neutrophil priming in host defense: role of oxidants as priming agents Antioxid. Redox. Signal. 4,69-83[CrossRef][Medline]
    90. 90
  90. Reumaux, D., Vossebeld, P. J. M., Roos, D., Verhoeven, A. J. (1995) Effect of tumor necrosis factor-induced integrin activation on Fc{gamma} receptor II-mediated signal transduction: relevance for activation of neutrophils by anti-proteinase-3 or anti-myeloperoxidase antibodies Blood 86,3189-3195[Abstract/Free Full Text]
    91. 91
  91. Csernok, E., Ernst, M., Schmitt, W., Bainton, D. F., Gross, W. L. (1994) Activated neutrophils express proteinase 3 on their plasma membrane in vitro and in vivo Clin. Exp. Immunol. 95,244-250[Medline]
    92. 92
  92. Porges, A. J., Redecha, P. B., Kimberly, W. T., Csernok, E., Gross, W. L., Kimberly, R. P. (1994) Anti-neutrophil cytoplasmic antibodies engage and activate human neutrophils via Fc{gamma}RIIa J. Immunol. 153,1271-1280[Abstract]
    93. 93
  93. Harper, L., Radford, D., Plant, T., Drayson, M., Adu, D., Savage, C. O. S. (2001) IgG from myeloperoxidase-antineutrophil cytoplasmic antibody-positive patients stimulates greater activation of primed neutrophils than IgG from proteinase 3-antineutrophil cytoplasmic antibody-positive patients Arthritis Rheum. 44,921-930[CrossRef][Medline]
    94. 94
  94. Hellmich, B., Csernok, E., Trabandt, A., Gross, W. L., Ernst, M. (2000) Granulocyte-macrophage colony-stimulating factor (GM-CSF) but not granulocyte colony-stimulating factor (G-CSF) induces plasma membrane expression of proteinase 3 (PR3) on neutrophils in vitro Clin. Exp. Immunol. 120,392-398[CrossRef][Medline]
    95. 95
  95. Csernok, E., Szymkowiak, C. H., Mistry, N., Daha, M. R., Gross, W. L., Kekow, J. (1996) Transforming growth factor-beta (TGF-ß) expression and interaction with proteinase 3 (PR3) in anti-neutrophil cytoplasmic antibody (ANCA)-associated vasculitis Clin. Exp. Immunol. 105,104-111[CrossRef][Medline]
    96. 96
  96. Deguchi, Y., Shibata, N., Kishimoto, S. (1990) Enhanced expression of the tumour necrosis factor/cachectin in peripheral blood mononuclear cells from patients with systemic vasculitis Clin. Exp. Immunol. 81,311-314[Medline]
    97. 97
  97. Noronha, I. L., Krüger, C., Andrassy, K., Ritz, E., Waldherr, R. (1993) In situ production of TNF{alpha}, IL-1ß, and IL-2R in ANCA-positive glomerulonephritis Kidney Int. 43,682-692[Medline]
    98. 98
  98. Luedke, E. S., Humes, J. L. (1989) Effect of tumor necrosis factor on granule release and LTB4 production in adherent human polymorphonuclear leukocytes Agents Actions 27,451-454[CrossRef][Medline]
    99. 99
  99. Hanlon, W. A., Stolk, J., Davies, P., Humes, J. L., Mumford, R., Bonney, R. J. (1991) rTNF alpha facilitates human polymorphonuclear leukocyte adherence to fibrinogen matrices with mobilization of specific and tertiary but not azurophilic granule markers J. Leukoc. Biol. 50,43-48[Abstract]
    100. 100
  100. Reumaux, D., Mull, F. P. J., Hordijk, P. L., Duthilleul, P., Roos, D. (2002) Effect of TNF-{alpha} on Fc{gamma} receptor IIa (Fc{gamma}RIIA) and ß2-integrin distribution on neutrophil surface analyzed by confocal laser scanning microscopy Clevel. Clin. J. Med. 69(Suppl. 2),SII-S163
    101. 101
  101. Reumaux, D., Tool, A. T. J., Hordijk, P. L., Duthilleul, P., Roos, D. (2002) Effect of priming by tumor necrosis factor on activation of human neutrophils by anti-proteinase-3 and anti-myeloperoxidase antibodies Anti-Neutrophil Cytoplasm Autoantibodies (ANCA). Clinical and Functional Studies. Ph.D. thesis ,95-121 University of Amsterdam The Netherlands.
    102. 102
  102. O’Flaherty, J. T., Rossi, A. G., Redman, J. F., Jacobson, D. P. (1991) Tumor necrosis factor-{alpha} regulates expression of receptors for formyl-methionyl-leucyl-phenylalanine, leukotriene B4, and platelet-activating factor. Dissociation from priming in human polymorphonuclear neutrophils J. Immunol. 147,3842-3847[Abstract]
    103. 103
  103. Elbim, C., Chollet-Martin, S., Bailly, S., Hakim, J., Gougerot-Pocidalo, M. A. (1993) Priming of polymorphonuclear neutrophils by tumor necrosis factor {alpha} in whole blood: identification of two polymorphonuclear neutrophil subpopulations in response to formyl-peptides Blood 82,633-640[Abstract/Free Full Text]
    104. 104
  104. Harper, L., Cockwell, P., Adu, D., Savage, C. O. S. (2001) Neutrophil priming and apoptosis in anti-neutrophil cytoplasmic autoantibody-associated vasculitis Kidney Int. 59,1729-1738[CrossRef][Medline]
    105. 105
  105. Borregaard, N., Lollike, K., Kjeldsen, L., Sengeløv, H., Bastholm, L., Nielsen, M. H., Bainton, D. F. (1993) Human neutrophil granules and secretory vesicles Eur. J. Haematol. 51,187-198[Medline]
    106. 106
  106. van de Winkel, J. G., Capel, P. J. (1993) Human IgG Fc receptor heterogeneity: molecular aspects and clinical implications Immunol. Today 14,215-221[CrossRef][Medline]
    107. 107
  107. Dijstelbloem, H. M., van de Winkel, J. G., Kallenberg, C. G. M. (2001) Inflammation in autoimmunity: receptors for IgG revisited Trends Immunol. 22,510-516[CrossRef][Medline]
    108. 108
  108. Maxwell, K. F., Powell, M. S., Hullet, M. D., Barton, P. A., McKenzie, I. F., Garrett, T. P., Hogarth, P. M. (1999) Crystal structure of the human leukocyte Fc receptor Fc{gamma}RIIa Nat. Struct. Biol. 6,437-442[CrossRef][Medline]
    109. 109
  109. van der Pol, W. L., van de Winkel, J. G. (1998) IgG receptor polymorphisms: risk factors for disease Immunogenetics 48,222-232[CrossRef][Medline]
    110. 110
  110. Dijstelbloem, H. M., Scheepers, R. H. M., Oost, W. W., Stegeman, C. A., van der Pol, W. L., Sluiter, W. J., Kallenberg, C. G. M., van de Winkel, J. G., Cohen Tervaert, J. W. (1999) Fc{gamma} receptor polymorphisms in Wegener’s granulomatosis: risk factors for disease relapse Arthritis Rheum. 42,1823-1827[CrossRef][Medline]
    111. 111
  111. Jayne, D. R., Weetman, A. P., Lockwood, C. M. (1991) IgG subclass distribution of autoantibodies to neutrophil cytoplasmic antigens in systemic vasculitis Clin. Exp. Immunol. 84,476-481[Medline]
    112. 112
  112. Brouwer, E., Cohen Tervaert, J. W., Horst, G., Huitema, M. G., van der Giessen, M., Limburg, P. C., Kallenberg, C. G. M. (1991) Predominance of IgG1 and IgG4 subclasses of anti-neutrophil cytoplasmic antibodies (ANCA) in patients with Wegener’s granulomatosis and clinically related disorders Clin. Exp. Immunol. 83,379-386[Medline]
    113. 113
  113. Mulder, A. H. L., Heeringa, P., Brouwer, E., Limburg, P. C., Kallenberg, C. G. M. (1994) Activation of granulocytes by anti-neutrophil cytoplasmic antibodies (ANCA): a Fc{gamma}RII-dependent process Clin. Exp. Immunol. 98,270-278[Medline]
    114. 114
  114. Kettritz, R., Jennette, J. C., Falk, R. J. (1997) Crosslinking of ANCA-antigens stimulates superoxide release by human neutrophils J. Am. Soc. Nephrol. 8,386-394[Abstract]
    115. 115
  115. Hulett, M. D., Hogarth, P. M. (1994) Molecular basis of Fc receptor function Adv. Immunol. 57,1-127[Medline]
    116. 116
  116. Wainstein, E., Edberg, J. C., Csernok, E., Sneller, M. C., Hoffmann, G. S., Keystone, E. C., Gross, W. L., Salmon, J. E., Kimberly, R. P. (1996) Fc{gamma}RIIIb alleles predict renal dysfunction in Wegener’s granulomatosis Arthritis Rheum. 39,S210
    117. 117
  117. Huizinga, T. W., van der Schoot, C. E., Jost, C., Klaassen, R., Kleijer, M., von dem Borne, A. E., Roos, D., Tetteroo, P. A. (1988) The PI-linked receptor Fc{gamma}RIII is released on stimulation of neutrophils Nature 333,667-669[CrossRef][Medline]
    118. 118
  118. Bazil, V., Strominger, J. L. (1994) Metalloprotease and serine protease are involved in cleavage of CD43, CD44, and CD16 from stimulated human granulocytes. Induction of cleavage of L-selectin via CD16 J. Immunol. 152,1314-1322[Abstract]
    119. 119
  119. Kocher, M., Edberg, J. C., Fleit, H. B., Kimberly, R. P. (1998) Antineutrophil cytoplasmic antibodies preferentially engage Fc{gamma}RIIIb on human neutrophils J. Immunol. 161,6909-6914[Abstract/Free Full Text]
    120. 120
  120. Kocher, M., Siegel, M. E., Edberg, J. C., Kimberly, R. P. (1997) Crosslinking of Fc{gamma}RIIa and Fc{gamma}RIIIb induces different proadhesive phenotypes on human neutrophils J. Immunol. 159,3940-3948[Abstract]
    121. 121
  121. Ben-Smith, A., Dove, S. K., Martin, A., Wakelam, M. J. O., Savage, C. O. S. (2001) Antineutrophil cytoplasm autoantibodies from patients with systemic vasculitis activate neutrophils through distinct signaling cascades: comparison with conventional Fc{gamma} receptor ligation Blood 98,1448-1455[Abstract/Free Full Text]
    122. 122
  122. Kimberly, R. P., Ahlstrom, J. W., Click, M. E., Edberg, J. C. (1990) The glycosyl phosphatidylinositol-linked Fc{gamma}RIIIPMN mediates transmembrane signaling events distinct from Fc{gamma}RII J. Exp. Med. 171,1239-1255[Abstract/Free Full Text]
    123. 123
  123. Watson, F., Gasmi, L., Edwards, S. W. (1997) Stimulation of intracellular Ca2+ levels in human neutrophils by soluble immune complexes: functional activation of Fc{gamma}RIIIb during priming J. Biol. Chem. 272,17944-17951[Abstract/Free Full Text]
    124. 124
  124. Edberg, J. C., Moon, J. J., Chang, D. J., Kimberly, R. P. (1998) Differential regulation of human neutrophil Fc{gamma}RIIa (CD32) and Fc{gamma}RIIIb (CD16) induced Ca2+ transients J. Biol. Chem. 273,8071-8079[Abstract/Free Full Text]
    125. 125
  125. Chuang, F. Y. S., Sassaroli, M., Unkeless, J. C. (2000) Convergence of Fc{gamma} receptor IIA and Fc{gamma} receptor IIIB signaling pathways in human neutrophils J. Immunol. 164,350-360[Abstract/Free Full Text]
    126. 126
  126. Salmon, J. E., Brogle, N. L., Edberg, J. C., Kimberly, R. P. (1991) Fc{gamma} receptor III induces actin polymerization in human neutrophils and primes phagocytosis mediated by Fc{gamma} receptor II J. Immunol. 146,997-1004[Abstract]
    127. 127
  127. Hundt, M., Schmidt, R. E. (1992) The glycosylphosphatidylinositol-linked Fc{gamma} receptor III represents the dominant receptor structure for immune complex activation of neutrophils Eur. J. Immunol. 22,811-816[Medline]
    128. 128
  128. van der Geld, Y. M., Limburg, P. C., Kallenberg, C. G. M. (2001) Proteinase 3, Wegener’s autoantigen: from gene to antigen J. Leukoc. Biol. 69,177-190[Abstract/Free Full Text]
    129. 129
  129. Cai, T-Q., Wright, S. D. (1996) Human leukocyte elastase is an endogenous ligand for the integrin CR3 (CD11b/CD18, Mac-1, {alpha}Mß2) and modulates polymorphonuclear leukocyte adhesion J. Exp. Med. 184,1213-1223[Abstract/Free Full Text]
    130. 130
  130. Johansson, M. W., Patarroyo, M., Öberg, F., Siegbahn, A., Nilsson, K. (1997) Myeloperoxidase mediates cell adhesion via the {alpha}Mß2 integrin (Mac-1, CD11b/CD18) J. Cell Sci. 110,1133-1139[Abstract]
    131. 131
  131. Clark, E. A., Brugge, J. S. (1995) Integrins and signal transduction pathways: the road taken Science 268,233-239[Abstract/Free Full Text]
    132. 132
  132. Annenkov, A., Ortlepp, S., Hogg, N. (1996) The beta 2 integrin Mac-1 but not p150,95 associates with Fc gamma receptor IIA Eur. J. Immunol. 26,207-212[Medline]
    133. 133
  133. Xue, W., Kindzielskii, A. L., Todd, R. F., Petty, H. R. (1994) Physical association of complement receptor type 3 and urokinase-type plasminogen activator receptor in neutrophil membranes J. Immunol. 152,4630-4640[Abstract]
    134. 134
  134. Yan, S. R., Fumagalli, L., Dusi, S., Berton, G. (1995) Tumor necrosis factor triggers redistribution to a Triton X-100-insoluble, cytoskeletal fraction of beta 2 integrins, NADPH oxidase components, tyrosine phosphorylated proteins, and the protein tyrosine kinase p58fgr in human neutrophils adherent to fibrinogen J. Leukoc. Biol. 58,595-606[Abstract]
    135. 135
  135. Skubitz, K. M., Campbell, K. D., Skubitz, A. P. N. (2000) CD63 associates with CD11/CD18 in large detergent-resistant complexes after translocation to the cell surface in human neutrophils FEBS Lett. 469,52-56[CrossRef][Medline]
    136. 136
  136. Barabé, F., Rollet-Labelle, E., Gilbert, C., Fernandes, M. J. G., Naccache, S. N., Naccache, P. H. (2002) Early events in the activation of Fc{gamma}RIIA in human neutrophils: stimulated insolubilization, translocation to detergent-resistant domains, and degradation of Fc{gamma}RIIA J. Immunol. 168,4042-4049[Abstract/Free Full Text]
    137. 137
  137. Zhou, M. J., Todd, R. F., van de Winkel, J. G. J., Petty, H. R. (1993) Cocapping of the leukoadhesin molecules complement receptor type 3 and lymphocye function-associated antigen-1 with Fc{gamma} receptor III on human neutrophils: possible role of lectin-like interactions J. Immunol. 150,3030-3041[Abstract]
    138. 138
  138. Zhou, M. J., Brown, E. J. (1994) CR3 (Mac-1, {alpha}Mß2, CD11b/CD18) and Fc{gamma}RIII cooperate in generation of a neutrophil respiratory burst: requirement for Fc{gamma}RII and tyrosine phosphorylation J. Cell Biol. 125,1407-1416[Abstract/Free Full Text]
    139. 139
  139. Skubitz, K. M., Campbell, K. D., Iida, J., Skubitz, A. P. N. (1996) CD63 associates with tyrosine kinase activity and CD11/CD18, and transmits an activation signal in neutrophils J. Immunol. 157,3617-3626[Abstract]
    140. 140
  140. Cao, D., Mizukami, I. F., Todd, R. F., Boxer, L. A., Petty, H. R. (1995) Human urokinase-type plasminogen activator primes neutrophils for superoxide anion release: possible roles of complement receptor type 3 and calcium J. Immunol. 154,1817-1829[Abstract]
    141. 141
  141. Kindzielskii, A. L., Laska, Z. O., Todd, R. F., Petty, H. R. (1996) Urokinase-type plasminogen activator receptor reversibly dissociates from complement receptor type 3 ({alpha}Mß2, CD11b/CD18) during neutrophil polarization J. Immunol. 156,297-309[Abstract]
    142. 142
  142. May, A. E., Kanse, S. M., Lund, L. R., Gisler, R. H., Imhof, B. A., Preissner, K. T. (1998) Urokinase receptor (CD87) regulates leukocyte recruitment via ß2 integrins in vivo J. Exp. Med. 188,1029-1037[Abstract/Free Full Text]
    143. 143
  143. Murray, J., Barbara, J. A. J., Dunkley, S. A., Lopez, A. F., van Ostatade, X., Condliffe, A. M., Dransfield, I., Haslett, C., Chilvers, E. R. (1997) Regulation of neutrophil apoptosis by tumor necrosis factor-alpha requirement for TNFR55 and TNFR75 for induction of apoptosis in vitro Blood 90,2772-2783[Abstract/Free Full Text]
    144. 144
  144. Thelen, M., Rosen, A., Nairn, A. C., Aderem, A. (1990) Tumor necrosis factor alpha modifies agonist-dependent responses in human neutrophils by inducing the synthesis and myristoylation of a specific protein kinase C substrate Proc. Natl. Acad. Sci. USA 87,5603-5607[Abstract/Free Full Text]
    145. 145
  145. Kettritz, R., Schreiber, A., Luft, F. C., Haller, H. (2001) Role of mitogen-activated protein kinases in activatio of human neutrophils by antineutrophil cytoplasmic antibodies J. Am. Soc. Nephrol. 12,37-46[Abstract/Free Full Text]
    146. 146
  146. Lloyds, D., Brindle, N. P. J., Hallet, M. B. (1995) Priming of human neutrophils by human tumour necrosis factor-{alpha} and substance P is associated with tyrosine phosphorylation Immunology 84,220-226[Medline]
    147. 147
  147. Yuo, A., Okuma, E., Kitagawa, S., Takaku, F. (1997) Tyrosine phosphorylation of p38 but not extracellular signal-regulated kinase in normal human neutrophils stimulated by tumor necrosis factor: comparative study with granulocyte-macrophage colony-stimulating factor Biochem. Biophys. Res. Commun. 235,42-46[CrossRef][Medline]
    148. 148
  148. Zu, Y. L., Qi, J., Gilelnist, A., Fernandez, G. A., Vazquez-Abad, D., Kreutzer, D. L., Huang, C. K., Sha’afi, R. I. (1998) p38 Mitogen-activated protein kinase activation is required for human neutrophil function triggered by TNF{alpha} or fMLP stimulation J. Immunol. 160,1982-1989[Abstract/Free Full Text]
    149. 149
  149. Radford, D. J., Lord, J. M., Savage, C. O. S. (1999) The activation of the neutrophil respiratory burst by anti-neutrophil cytoplasm autoantibody (ANCA) from patients with systemic vasculitis requires tyrosine kinases and protein kinase C activation Clin. Exp. Immunol. 118,171-179[CrossRef][Medline]
    150. 150
  150. Kettritz, R., Choi, M., Butt, W., Rane, M., Rolle, S., Luft, F. C., Klein, J. B. (2002) Phosphatidylinositol 3-kinase controls antineutrophil cytoplasmic antibodies-induced respiratory burst in human neutrophils J. Am. Soc. Nephrol. 13,1740-1749[Abstract/Free Full Text]
    151. 151
  151. Gewirtz, A. T., Simons, E. R. (1997) Phospholipase D mediates Fc{gamma} receptor activation of neutrophils and provides specificity between high-valency immunecomplexes and fMLP signaling pathways J. Leukoc. Biol. 61,522-528[Abstract]
    152. 152
  152. Tilton, B., Andjelkovic, M., Didichenko, S. A., Hemmings, B. A., Thelen, M. (1997) G-Protein-coupled receptors and Fcgamma-receptors mediate activation of Akt/protein kinase B in human phagocytes J. Biol. Chem. 272,28096-28101[Abstract/Free Full Text]
    153. 153
  153. Grimminger, F., Hattar, K., Papavassilis, C., Temmesfeld, B., Csernok, E., Gross, W. L., Seeger, W., Sibelius, U. (1996) Neutrophil activation by anti-proteinase 3 antibodies in Wegener’s granulomatosis: role of exogenous arachidonic acid and leukotriene B4 generation J. Exp. Med. 184,1567-1572[Abstract/Free Full Text]
    154. 154
  154. Yang, J. J., Preston, G. A., Alcorta, D. A., Waga, I., Munger, W. E., Hogan, S. L., Sekura, S. B., Phillips, B. D., Thomas, R. P., Jennette, J. C., Falk, R. J. (2002) Expression profile of leukocyte genes activated by anti-neutrophil cytoplasmic autoantibodies (ANCA) Kidney Int. 62,1638-1649[CrossRef][Medline]
    155. 155
  155. Franssen, C. F., Gans, R. O., Arends, B., Hageluken, C., ter Wee, P. M., Gerlag, P. G., Hoorntje, S. J. (1995) Differences between anti-myeloperoxidase and anti-proteinase 3-associated renal disease Kidney Int. 47,193-199[Medline]
    156. 156
  156. Franssen, C. F., Gans, R. O., Kallenberg, C. G. M., Hageluken, C., Hoorntje, S. J. (1998) Disease spectrum of patients with antineutrophil cytoplasmic autoantibodies of defined specificity: distinct differences between patients with anti-proteinase 3 and anti-myeloperoxidase autoantibodies J. Intern. Med. 244,209-216[CrossRef][Medline]
    157. 157
  157. Franssen, C. F., Stegeman, C. A., Kallenberg, C. G., Gans, R. O., de Jong, P. E., Hoorntje, S. J., Cohen Tervaert, J. W. (2000) Antiproteinase 3- and antimyeloperoxidase-associated vasculitis Kidney Int. 57,2195-2206[CrossRef][Medline]
    158. 158
  158. Franssen, C. F., Huitema, M. G., Muller Kobold, A. C., Oost-Kort, W. W., Limburg, P. C., Tiebosch, A., Stegeman, C. A., Kallenberg, C. G., Cohen Tervaert, J. W. (1999) In vitro neutrophil activation by antibodies to proteinase 3 and myeloperoxidase from patients with crescentic glomerulonephritis J. Am. Soc. Nephrol. 10,1506-1515[Abstract/Free Full Text]
    159. 159
  159. Reumaux, D., de Boer, M., Duthilleul, P., Roos, D. (2002) Expression of myeloperoxidase (MPO) by neutrophils is necessary for their activation by anti-neutrophil cytoplasm autoantibodies (ANCA) against MPO Anti-Neutrophil Cytoplasm Autoantibodies (ANCA). Clinical and Functional Studies. Ph.D. thesis ,131-148 University of Amsterdam The Netherlands.
    160. 160
  160. Mulder, A. H. L., Stegeman, C. A., Kallenberg, C. G. M. (1995) Activation of granulocytes by anti-neutrophil cytoplasmic antibodies (ANCA) in Wegener’s granulomatosis: a predominant role for the IgG3 subclass of ANCA Clin. Exp. Immunol. 101,227-232[Medline]
    161. 161
  161. Ewert, B. H., Becker, M. E., Jennette, J. C., Falk, R. J. (1995) Antimyeloperoxidase antibodies induce neutrophil adherence to cultured human endothelial cells Ren. Fail. 17,125-133[Medline]
    162. 162
  162. Radford, D. J., Savage, C. O. S., Nash, G. B. (2000) Treatment of rolling neutrophils with antineutrophil cytoplasmic antibodies causes conversion to firm integrin-mediated adhesion Arthritis Rheum. 43,1337-1345[CrossRef][Medline]
    163. 163
  163. Radford, D. J., Luu, N. T., Hewins, P., Nash, G. B., Savage, C. O. S. (2001) Antineutrophil cytoplasmic antibodies stabilize adhesion and promote migration of flowing neutrophils on endothelial cells Arthritis Rheum. 44,2851-2861[CrossRef][Medline]
    164. 164
  164. Johnson, R. J., Couser, W. G., Chi, E. Y., Adler, S., Klebanoff, S. J. (1987) New mechanism for glomerular injury. Myeloperoxidase-hydrogen peroxide-halide system J. Clin. Invest. 79,1379-1387
    165. 165
  165. Savage, C. O. S., Pottinger, B. E., Gaskin, G., Pusey, C. D., Pearson, J. D. (1992) Autoantibodies developing to myeloperoxidase and proteinase 3 in systemic vasculitis stimulate neutrophil cytotoxicity towards cultured endothelial cells Am. J. Pathol. 141,335-342[Abstract]
    166. 166
  166. Savage, C. O. S., Gaskin, G., Pusey, C. D., Pearson, J. D. (1993) Anti-neutrophil cytoplasm antibodies can recognize vascular endothelial cell-bound anti-neutrophil cytoplasm antibody-associated autoantigens Exp. Nephrol. 1,190-195[Medline]
    167. 167
  167. Varani, J., Ginsburg, I., Schuger, L., Gibbs, D. F., Bromberg, J., Johnson, K. J., Ryan, U. S., Ward, P. A. (1989) Endothelial cell killing by neutrophils: synergistic interaction of oxygen products and proteases Am. J. Pathol. 135,435-438[Abstract]
    168. 168
  168. Westlin, W., Gimbrone, M. J. (1993) Neutrophil-mediated damage to human vascular endothelium: role of cytokine activation Am. J. Pathol. 142,117-128[Abstract]
    169. 169
  169. Ballieux, B. E. P. B., Hiemstra, P. S., Klar-Mohamad, N., Hagen, E. C., van Es, L. A., van der Woude, F. J., Daha, M. R. (1994) Detachment and cytolysis of human endothelial cells by proteinase 3 Eur. J. Immunol. 24,3211-3215[Medline]
    170. 170
  170. Kao, R. C., Wehner, N. G., Skubitz, K. M., Gray, B. H., Hoidal, J. R. (1989) Proteinase 3. A distinct human polymorphonuclear leukocyte proteinase that produces emphysema in hamsters J. Clin. Invest. 82,1963-1973
    171. 171
  171. Abrahamson, D., Irwin, M., Blackburn, W., Heck, L. (1990) Degradation of basement membrane laminin by human elastase and cathepsin G Am. J. Pathol. 143,1267-1274
    172. 172
  172. Rao, N. V., Wehner, N. G., Marshall, B. C., Gray, W. R., Gray, B. H., Hoidal, J. R. (1991) Characterization of proteinase-3 (PR-3), a neutrophil serine proteinase J. Biol. Chem. 266,9540-9548[Abstract/Free Full Text]
    173. 173
  173. Yang, J. J., Kettritz, R., Falk, R. J., Jennette, J. C., Gaido, M. L. (1996) Apoptosis of endothelial cells induced by the neutrophil serine proteases proteinase 3 and elastase Am. J. Pathol. 149,1617-1626[Abstract]
    174. 174
  174. Taekema-Roelvink, M. E. J., van Kooten, C., Janssens, M. C., Heemskerk, E., Daha, M. R. (1998) Effect of anti-neutrophil cytoplasmic antibodies on proteinase 3-induced apoptosis of human endothelial cells Scand. J. Immunol. 48,37-43[CrossRef][Medline]
    175. 175
  175. Yang, J. J., Segelmark, M., Preston, G., Jennette, J. C., Falk, R. J. (1998) Proteinase 3 (PR3) and myeloperoxidase (MPO) cross the membrane of endothelial cells and PR3 but not MPO triggers apoptosis Clin. Exp. Immunol. 112(Suppl. 1),46
    176. 176
  176. Pendergraft, W. F., Zarella, C. S., Yang, J. J., Falk, R. J., Jennette, J. C., Preston, G. A. (2000) Proteolytically inactive C-terminal death domain of proteinase 3 Clin. Exp. Immunol. 120(Suppl. 1),37
    177. 177
  177. Eiserich, J., Hristova, M., Cross, C., Jones, A. D., Freeman, B. A., Halliwell, B., van der Vliet, A. (1998) Formation of nitric oxide-derived inflammatory oxidants by myeloperoxidase in neutrophils Nature 391,383-397
    178. 178
  178. van de Wiel, B. A., Dolman, K. M., van der Meer Gerritsen, C. H., Hack, C. E., von dem Borne, A. E. G. K., Goldschmeding, R. (1992) Interference of Wegener’s granulomatosis autoantibodies with neutrophil proteinase 3 activity Clin. Exp. Immunol. 90,409-414[Medline]
    179. 179
  179. Dolman, K. M., Stegeman, C. A., van de Wiel, B. A., Hack, C. E., von dem Borne, A. E. G. K., Kallenberg, C. G. M., Goldschmeding, R. (1993) Relevance of classic anti-neutrophil cytoplasmic autoantibody (C-ANCA)-mediated inhibition of proteinase 3-alpha 1-antitrypsin complexation to disease activity in Wegener’s granulomatosis Clin. Exp. Immunol. 93,405-410[Medline]
    180. 180
  180. Daouk, G. H., Palsson, R., Arnaout, M. A. (1995) Inhibition of proteinase 3 by ANCA and its correlation with disease activity in Wegener’s granulomatosis Kidney Int. 47,1528-1536[Medline]
    181. 181
  181. van der Geld, Y. M., Tool, A. T. J., Videler, J., de Haas, M., Cohen Tervaert, J. W., Stegeman, C. A., Limburg, P. C., Kallenberg, C. G. M., Roos, D. (2002) Interference of PR3-ANCA with the enzymatic activity of PR3: differences in patients during active disease or remission of Wegener’s granulomatosis Clin. Exp. Immunol. 129,562-570[CrossRef][Medline]
    182. 182
  182. Chapman, P. T., Short, A. K., Lockwood, C. M. (1998) The use of biosensor technology in epitope mapping studies on human myeloperoxidase Clin. Exp. Immunol. 112(Suppl. 1),44[CrossRef][Medline]
    183. 183
  183. Griffin, S. V., Chapman, P. T., Lianos, E. A., Lockwood, C. M. (1999) The inhibition of myeloperoxidase by celuroplasmin can be reversed by anti-myeloperoxidase antibodies Kidney Int. 55,917-925[CrossRef][Medline]
    184. 184
  184. Rooney, C. P., Taggart, C., Coakley, R., McElvaney, N. G., O’Neill, S. J. (2001) Anti-proteinase 3 antibody activation of neutrophils can be inhibited by alpha1-antitrypsin Am. J. Respir. Cell Mol. Biol. 24,747-754[Abstract/Free Full Text]
    185. 185
  185. Esnault, V. L. M., Testa, A., Audrain, A., Roge, C., Hamidou, M., Barrier, J. H., Sesboue, R., Martin, J. P., Lesavre, P. (1993) Alpha1-antitrypsin genetic polymorphism in ANCA-positive systemic vasculitis Kidney Int. 43,1329-1332[Medline]
    186. 186
  186. Harper, L., Ren, Y., Savill, J., Adu, D., Savage, C. O. S. (2000) Antineutrophil cytoplasmic antibodies induce reactive oxygen-dependent dysregulation of primed neutrophil apoptosis and clearance by macrophages Am. J. Pathol. 157,211-220[Abstract/Free Full Text]
    187. 187
  187. Moosig, F., Csernok, E., Kumanovics, G., Gross, W. L. (2000) Opsonization of apoptotic neutrophils by anti-neutrophil cytoplasmic antibodies (ANCA) leads to enhanced uptake by macrophages and increased release of tumour necrosis factor-alpha (TNF-{alpha}) Clin. Exp. Immunol. 122,499-503[CrossRef][Medline]
    188. 188
  188. Kettritz, R., Scheumann, J., Xu, Y., Luft, F. C., Haller, H. (2002) TNF{alpha}-accelerated apoptosis abrogates ANCA-mediated neutrophil respiratory burst by a caspase-dependent mechanism Kidney Int. 61,502-515[CrossRef][Medline]
    189. 189
  189. Gilligan, H. M., Bredy, B., Brady, H. R., Hebert, M. J., Slayter, H. S., Xu, Y., Rauch, J., Shia, M. A., Koh, J. S., Levine, J. S. (1996) Antineutrophil cytoplasmic autoantibodies interact with primary granule constituents on the surface of apoptotic neutrophils in the absence of neutrophil priming J. Exp. Med. 184,2231-2241[Abstract/Free Full Text]
    190. 190
  190. Yang, J. J., Tuttle, R. H., Hogan, S. L., Taylor, J. G., Phillips, B. D., Falk, R. J., Jennette, J. C. (2000) Target antigens for anti-neutrophil cytoplasmic autoantibodies (ANCA) are on the surface of primed and apoptotic but not unstimulated neutrophils Clin. Exp. Immunol. 121,165-172[CrossRef][Medline]



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