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(Journal of Leukocyte Biology. 2001;69:177-190.)
© 2001 by Society for Leukocyte Biology

Proteinase 3, Wegener’s autoantigen: from gene to antigen

Y. M. van der Geld, P. C. Limburg and C. G. M. Kallenberg

Department of Internal Medicine, University Hospital Groningen, The Netherlands

Correspondence: Ymke van der Geld, Department of Clinical Immunology, University Hospital Groningen, Hanzeplein 1, 9713GZ Groningen, The Netherlands. E-mail: Y.M.van.der.geld{at}med.rug.nl


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ABSTRACT
 
Proteinase 3 (PR3) is one of four serine protease homologues in the azurophilic granules of neutrophils and granules of monocytes. It is of importance that anti-neutrophil cytoplasmic antibodies (ANCA) in patients with Wegener’s granulomatosis (WG) are mainly directed against PR3 only. Furthermore, PR3 is overexpressed in a variety of acute and chronic myeloid leukemia cells. Cytotoxic T lymphocytes specific for a PR3-derived peptide have been shown to specifically lyse leukemia cells that overexpress PR3. This review will focus on PR3 and the characteristics of PR3 that might implicate this particular antigen in the pathogenesis of WG and as target for immunotherapy in myeloid leukemias. We will discuss the genetic localization and gene regulation of PR3, the processing, storage, and expression of the PR3 protein, and the physiological functions of PR3, and compare this with the three other neutrophil-derived serine proteases: human leukocyte elastase, cathepsin G, and azurocidin. Three main differences are described between PR3 and the other serine proteases. This makes PR3 a very intriguing protein with a large array of physiological functions, some of which may play a role in ANCA-associated vasculitidis and myeloid leukemia.

Key Words: Wegener’s granulomatosis • myeloid leukemia • serine protease


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INTRODUCTION
 
Proteinase 3 (PR3) is one of the four neutral serine protease homologues [1 ] that are localized in the azurophilic granules of neutrophils and the granules of monocytes [2 3 4 ]. PR3 (EC3.4.21) was shown to be identical to neutrophil proteinase p29 [5 , 6 ], azurophilic granule protein 7 (AGP-7) [7 ], and myeloblastin [5 , 6 , 8 ]. PR3 was originally described as a protein that degrades elastin with relevance for the pathogenesis of human emphysema [9 ], and p29 was identified as the autoantigen in Wegener’s granulomatosis (WG) [10 ]. AGP-7 was mentioned as one of the microbicidal proteins in the azurophilic granules of the neutrophil [11 ], and myeloblastin as a serine proteinase involved in the control of growth and differentiation of human leukemic cells [12 ]. Thus, PR3 is an important protein both in WG and myeloid leukemia, and has a whole array of physiological and, possibly, pathophysiological functions.

Friedrich Wegener first described WG in 1936 as a distinct entity within the group of primary vasculitides. WG is characterized by granulomatous inflammation in the upper and lower respiratory tract, systemic vasculitis affecting small blood vessels, and pauci-immune necrotizing crescentic glomerulonephritis [13 ]. The research on WG took a big leap forward when van der Woude and colleagues in 1985 established the close association between active WG and anti-neutrophil cytoplasmic antibodies (ANCA) [14 ]. The discovery of these autoantibodies suggested an autoimmune pathogenesis for WG. Five years later the target antigen for ANCA in WG was identified as PR3 [10 , 15 , 16 ]. PR3-ANCA has been established as a specific marker for WG, and detection of these autoantibodies is helpful in the diagnosis and follow-up of WG patients [17 , 18 ]. Furthermore, in most cases a strong correlation has been observed between PR3-ANCA and disease activity of WG as titers of PR3-ANCA rise before a relapse of WG in many patients [17 , 19 20 21 22 ]. Also, PR3-reactive T cells have been reported in patients with WG [23 24 25 26 ].

It is interesting that PR3 is overexpressed in a variety of acute and chronic myeloid leukemia cells [27 ]. In 1996 Ballieux et al. [24 ] identified several PR3-derived peptides restricted to HLA-A2. Cytotoxic T lymphocytes (CTL) specific for one of these HLA-A2-restricted peptides derived from PR3 preferentially lysed chronic myeloid leukemia cells [28 ] and also inhibited granulocyte-macrophage colony-forming unit activity from HLA-A2+ patients with chronic myeloid leukemia [29 ]. The extent of lysis and colony inhibition was proportional to PR3 overexpression in leukemia cells. Furthermore, an HLA-A2-PR3-peptide tetramer could be used to identify and select PR3-specific CTLs from healthy donors, which could be used in leukemia-specific adoptive immunotherapy [30 , 31 ].

So, PR3 has been implicated in two diseases either as autoantigen or as target for immunotherapy. Most reviews on PR3-ANCA have focused on the autoantibodies in ANCA-associated vasculitis. This review will focus on PR3 and the characteristics of PR3 that might implicate this particular antigen, and not other neutrophil-derived serine proteinases, in the pathogenesis of WG, and as target for immunotherapy in myeloid leukemias. We will discuss three main subjects: namely, the genetic localization and gene regulation of PR3, the processing, storage, and expression of the PR3 protein, and the physiological functions of PR3.


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GENE LOCALIZATION AND GENE REGULATION
 
Gene localization
In human neutrophilic granulocytes and monocytes four serine protease homologues are present, namely PR3, human neutrophil elastase (HLE), azurocidin (AZU), and cathepsin G (CatG). These four proteins share a large sequence homology [32 ]. The gene for PR3 is localized on chromosome 19p13.3 [33 ] in a cluster with HLE and AZU [34 ]. The gene for CatG is localized on chromosome 14q11.2 [35 ]. Genes for PR3, HLE, and AZU are transcribed in the same orientation and share the same number of exons. The PR3 gene spans 6570 base pairs and consists of five exons and four introns. Each residue of the catalytic triad of PR3, that is H44, D91, and S176, is located on a separate exon, classifying PR3 in class 6 of the trypsin superfamily (see Fig. 1 B ). The PR3 gene is larger than genes for CatG [35 ] and HLE [36 , 37 ] due to a considerably larger size of introns I and III. The PR3 gene, compared to the HLE gene, contains two large tracts in intron I and intron IV of unusual sequence [38 ]. Intron I contains an area consisting of two repeating motifs: GAAT and TGAGT. Intron IV includes a region of 12 GA repeats. These tracts may cause chromosomal instability and perhaps predisposition to genetic rearrangements and deletions similar to those associated with leukemia [39 ].



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  		Figure 1. Structure of the PR3 promoter region, gene, and protein. (A) Promotor region of PR3 with its regulatory elements in solid boxes and flanking sequences as lines. The boxes for the ß-globulin elements are hatched. The CG-element and PU.1 element boxes are black and gray, respectively. Exon I is shown as a light gray box. The numbers next to the promoter region indicate the base pairs of the PR3 sequence where the regulatory elements are located [34 , 47 ]. (B) Structure of the PR3 gene. Gray boxes indicate exons with the exon number in the box. Introns and flanking sequences are shown as lines. The numbers next to the gene structure indicate the base pairs forming each intron and exon. The promoter region of PR3 is enlarged in panel A. (C) The protein structure of PR3. The signal sequence, prosequences, and carboxy-terminal sequence are shown as gray, black, and stippled boxes, respectively. Exons are indicated with the exon number in the box. The amino acids, H44, D91, and S176 forming the catalytic triad are indicated with arrows, and the two glycosylation sites on N102 and N147 are indicated with lines [38 ]. SS indicates disulfide bridges. The numbers next to the protein structure indicate the amino acids of the PR3 sequence [12 , 32 ].

Allelic variation in the PR3 locus may well be associated with quantitative and/or qualitative differences in the expression pattern of PR3 during myeloid development. Variations in the promoter region and cis-acting regulatory elements of the PR3 gene causing quantitative differences in PR3 expression have thus far not been identified. Nonetheless, allelic variation in the coding regions of the PR3 gene may occur. Three amino acid variations were found between the myeloblastin cDNA [12 ] and the reported PR3 cDNA [32 , 38 ] (Table 1 ). One of these variations was recently confirmed by Clave et al. who looked at these variations in the PR3 sequence as a potential target for T cell alloresponses to myeloid leukemia [31 ]. Furthermore, a bi-allelic restriction fragment length polymorphism (RFLP) was described in the PR3 gene [40 ]. It is not known whether this RFLP of the PR3 gene is related to variations in amino acid sequence, but this polymorphism might reflect one of the three described variations in the amino acid sequence of PR3. Polymorphism in coding regions of HLE or CatG causing an aberrant amino acid sequence has thus far not been reported.


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  		Table 1. Polymorphisms in Amino Acids of the PR3 Sequence

So, PR3, HLE, and CatG are not very polymorphic proteins because almost no variations have been described in their amino acid sequence. Still, the variability in the PR3 protein is located in close vicinity to the active site aspartic acid residue and may thus affect the catalytic site of PR3. These amino acid variations may affect the function of PR3 and may make PR3 less accessible for inhibitors like {alpha}1-antitrypsin. So it is possible that these variants of PR3 differ in their potential to damage connective tissues, which could lead to more damage. However, this has to be further investigated.

Gene regulation
The mRNA of PR3 is expressed in early cells of the myeloid and monocytic lineage [8 , 38 , 41 ]. Transcription of PR3, together with HLE, CatG, and myeloperoxidase (MPO), is restricted to the promyelocyte and promonocyte stage of myeloid differentiation, and transcription is down-regulated upon granulocyte and monocyte maturation [12 , 34 , 42 ]. It has been shown that mRNA expression of PR3 is tightly down-regulated once the promyelocytic cell lines, HL60 [8 , 12 , 43 44 45 ] and NB4 [43 ], or the promonocytic cell lines, U937 [8 , 34 ] and THP-1 [45 ], are treated with dimethyl sulfoxide (DMSO) [12 , 44 ] or retinoic acid [12 , 43 ] to induce granulocyte differentiation. Also, treatment with 1,25-dihydroxyvitamin D3 [1,25-(OH)2D3] [8 , 12 ], PMA [8 , 12 , 34 ], 12-O-tetradecanoylphorbol 13-acetate (TPA) [44 ], or bile acids [45 ], all of which induce monocyte differentiation, caused down-regulation of PR3 mRNA expression. This tight control of the PR3 mRNA expression was shown to be effective at the transcriptional as well as at the posttranscriptional level [43 , 44 ]. Therefore, the PR3 gene belongs to a group of genes that are directly and negatively regulated during myeloid differentiation [44 ], as has previously been shown for the MPO gene [46 ].

Recently, the transcriptional control of the PR3 gene has been analyzed. The 5’ flanking region of the PR3 gene contains a TATA-box [34 , 38 , 47 ], a PU.1 regulatory element, a CG-element, and a potential site for the CAAT binding protein (C/EBP) and c-Myb transcription factors. The CAAT box promoter element, which is present in the promoter regions of HLE [36 ] and CatG [35 ], is not present in the PR3 promoter. Furthermore, the 5’ region of the PR3 gene includes a NF-{kappa}B element on the antisense strand, five ß-globulin-specific elements, and two ets-core elements. Three of the five ß-globulin elements are preceded by a thymine, forming the retinoic acid regulatory elements [34 , 47 ]. The 5’ flanking region of PR3 is outlined in Figure 1A .

Within the base pairs -200 to 1 of the PR3 promoter, two elements were identified that are sufficient for maximal expression of PR3 mRNA. These two elements are a PU.1 consensus located at position -101 and a CG-element located at position -190 [47 ]. The PU.1 consensus binds a myeloid nuclear protein, the transcription factor PU.1, which is expressed in myeloid and B cells but not T cells [48 ]. The CG-element binds a nuclear protein of ~40 kDa that is found in myeloid as well as non-myeloid cells such as HeLa cells. The CG-element is complementary to the binding site of the transcription factor Sp1, but in the PR3 promoter region no binding of Sp1 could be observed. The activity of these two elements is dependent on the presence of the -91 to 0 promoter region, which contains the potential sites for C/EBP and c-Myb and the TATA box [47 ].

In the CatG promoter the C/EBP and c-Myb sites are not present, whereas the PU.1 and CG-elements are present in both the HLE [36 ] and the CatG [35 ] promoter regions. This suggests that the latter sites are important control elements for tissue- and developmental stage-specific expression of the neutrophil and monocyte specific serine proteases.

Because PR3 [47 ], HLE [36 , 37 ], CatG [35 ], and MPO [49 ] are similarly regulated during myeloid differentiation most of the regulatory elements present in the promoter region are alike. Nonetheless, there are some minor differences (shown in Table 2 ), two of which were already mentioned above. A glucocorticoid-response element and an ocotomer-binding factor response element present in the CatG and HLE genes are not present in the PR3 gene [34 , 38 ]. The significance of these differences in regulatory elements between the PR3 gene and the genes for HLE, CatG, and MPO is not known. These differences could be important for differential regulation of the PR3 gene, which might have implication for possible aberrant expression of PR3 in patients with WG and myeloid leukemia.


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  		Table 2. Transcriptional Control Elements Present in the 5' Flanking Promoter Region of PR3, HLE, CatG, and MPO

The mechanisms directing the high level of transcription of PR3 and other neutrophil-derived serine proteases in myeloid cells committed to granulocyte differentiation is poorly understood. The transcription of PR3 may in part be regulated by developmental stage-specific expression of transcription factors like PU.1 and the transcription factor binding to the CG-element as described above. Furthermore, transcription of PR3, HLE, and AZU is regulated by changes in chromatin structure in the gene cluster, which were identified as DNase I hypersensitive sites [50 ], and changes in cytosine-methylation of the PR3 locus [51 ]. Normally, demethylation and subsequent methylation of certain gene clusters regulate gene transcription. However, in mature neutrophils and monocytes the PR3 locus is completely demethylated [51 ] and in the PR3-HLE-AZU gene cluster DNase I hypersensitive sites could no longer be detected [50 ].


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PROCESSING, STORAGE, AND EXPRESSION OF PR3
 
Processing and storage of PR3
The expression of PR3 is restricted to cells of the granulocytic and monocytic lineage [27 , 52 ]. Upon maturation of the cells PR3 is present in monocytes and granulocytes [53 ]. In these cells PR3 co-localizes with MPO, HLE, and CatG in granules of monocytes [54 , 55 ] and the azurophilic granules of granulocytes [54 55 56 ]. In these granules PR3 is stored as a mature and potentially enzymatic active protein [15 ].

Processing and granular sorting of PR3 is very similar to that of HLE [57 ], CatG [57 , 58 ], and AZU [59 ] [reviewed in refs. 60 61 62 ]. The processing of PR3 is depicted in Figure 2 . During translation PR3 is synthesized as a prepro-enzyme, shown in Figure 1C . The prepro-enzyme of PR3 is processed in four consecutive steps into a mature form consisting of 222 amino acids. First, the signal peptide is removed upon translocation of prepro-PR3 into the endoplasmic reticulum (ER), yielding a pro-form of PR3 with an amino-terminal and carboxy-terminal propeptide [63 , 64 ]. The amino-terminal propeptide of two amino acids, Ala-Glu for PR3, is a typical feature of myeloid serine proteases [65 , 66 ]. Next, PR3 is glycosylated on both its potential sites for N-linked glycosylation. High-mannose oligosaccharide side chains are added in the ER and converted into complex saccharide chains with terminal sialic acid residues in the Golgi complex [15 , 63 , 64 , 67 ]. As a third processing step the propeptide of PR3 is removed in the post-Golgi organelle [63 , 64 ]. The enzyme responsible for the removal of this propeptide is a cysteine proteinase distinct from dipeptidyl peptidase I (DPPI), which cleaves the propeptide of CatG [68 ], HLE [57 ], and AZU [59 ]. After removal of the two amino acid propeptide the substrate-binding pocket becomes accessible and PR3 becomes potentially enzymatically active [63 , 64 , 69 ]. As a fourth step, a seven-amino-acid carboxy-terminal extension is removed during processing of PR3 [63 , 64 ]. Cleavage takes place next to Arg222, suggesting that a trypsin-like proteinase is involved in the carboxy-terminal processing of PR3. During processing of PR3 four disulfide bridges are formed keeping its three-dimensional structure intact (Fig. 3 ). In the acidic environment of the azurophilic granules the mature form of PR3 is maintained in a conformationally inactive form. Upon translocation into neutral pH PR3 undergoes a final conformational change into an active form. This pH-dependent phenomenon has thus far only been described for PR3 [70 ].



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  		Figure 2. Schematic model illustrating processing of PR3. The signal peptide is removed upon translocation of prepro-PR3 in the endoplasmic reticulum (ER). In the ER and Golgi PR3 is glycosylated with high-mannose oligosaccharides, which are converted into complex oligosaccharides. The propeptide and carboxy-terminal extension are removed in a post-Golgi organelle. PR3 is stored in the granules as an active enzyme. PR3 can also be secreted as a partially processed pro-form [reviewed in refs. 61 62 ]. PR3 is also expressed in the secretory vesicles and specific granules and PR3 is expressed on the plasma membrane.



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  		Figure 3. Three-dimensional model of PR3 according to the coordinates provided by Fujinaga et al. [69 ]. Amino acids are numbered in agreement with the PR3 sequence published by Campanelli et al. [32 ]. {alpha}-Helixes are shown in red and the ß-sheets are shown in green. The amino acids His44, Asp91, and Ser176 form the catalytic triad of PR3._art>

The various processing steps of PR3 and other serine proteases have been analyzed in their role in granular targeting and storage of these proteins. Elimination of the functional glycosylation site of CatG [71 ] or PR3 [72 ] had no obvious consequences for granular targeting [63 ]. Furthermore, deletion of the carboxy-terminal extension of CatG and HLE [73 ], and deletion of the propeptide of CatG [61 , 74 ] did not influence the targeting of the serine proteases to granules. Consequently, a specific targeting mechanism for PR3 and other neutrophil and monocyte-derived serine proteases to the granules has not been revealed.

It is interesting that during synthesis minor portions of the pro-form of PR3 [63 , 64 , 75 ] and other neutrophil- and monocyte-derived serine proteases [57 , 58 , 68 ] escape granular targeting and are secreted (Fig. 2) . This phenomenon has been regarded as an imperfection of the granular targeting process. Recently a function of the secreted pro-form of PR3 was described as being a putative negative feedback regulator of granulopoiesis [75 ] (see below). The overwhelming majority of PR3 is stored in the azurophilic granules as a mature form without amino- and carboxy-terminal propeptides. The secreted form of PR3, however, still contains the amino-terminal propeptide. This pro-form of PR3 is probably targeted for secretion before the post-Golgi organelle and may thus also still have the carboxy-terminal extension.

Only recently it was shown that PR3 is not only stored in the azurophilic granules but is also present in secretory vesicles and in the specific granules, whereas MPO and HLE were only present in azurophilic granules [76 ]. Whether this PR3 in the secretory and specific granules is comparable to the secreted pro-form of PR3 or the mature form of PR3 stored in the azurophilic granules still has to be established.

PR3 migrates on a sodium dodecyl sulfate-polyacrylamide gel electrophoresis (SDS-PAGE) gel as a triplet of approximately 29–32 kDa. These isoforms probably differ in their carbohydrate structures, as has been shown for HLE and CatG [77 ]. In HLE and CatG certain isoforms were destined for granular targeting and others for secretion. Glycosylation isoforms of PR3 may underlie differences in targeting of PR3. So certain isoforms of PR3 may be destined for granular targeting and others for secretion or expression on the plasma membrane. This might explain the differential expression of PR3 in neutrophils and monocytes.

Differences in processing and storage between PR3, HLE, CatG, and MPO are summarized in Table 3 . In summary, PR3, in contrast to HLE, CatG, and MPO is also present in the secretory vesicles and specific granules. Upon activation these secretory vesicles are readily degranulated, and PR3 might be translocated to the plasma membrane. PR3-ANCA in WG patients can bind to these membrane-bound and secreted forms of PR3. The existence of this readily mobilized pool of PR3 might thus play a relevant role in the pathophysiology of WG.


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  		Table 3. Differences in Processing, Storage, and Expression Between PR3, HLE, CatG, and MPO

Membrane expression of PR3
Apart from the presence of PR3 in azurophilic granules and secretory vesicles, PR3 expression was also observed on the plasma membrane of resting neutrophils [54 , 76 ] and monocytes [78 ]. This PR3 expression on neutrophils was increased in patients with active WG [79 , 80 ] and the expression of PR3 correlated with disease activity [79 ]. In contrast, no membrane expression for HLE, MPO [76 , 79 , 80 ] or AZU [81 ] was observed on resting neutrophils.

On resting neutrophils of healthy controls a clear bimodal distribution of PR3 surface expression has been observed [82 , 83 ]. Three distinct phenotypes of donors could be defined corresponding to a low, i.e. less than 20% of neutrophils with membrane PR3 (mPR3), intermediate, and high percentage of mPR3-expressing neutrophils. These distinct phenotypes of mPR3 expressing neutrophils varied among individuals, and a particular phenotype was extremely stable for each individual in time as well as after neutrophil activation. This peculiar type of distribution seems to be restricted to PR3 and might be genetically controlled [82 , 83 ]. The occurrence of a high percentage of neutrophils expressing mPR3 is increased in patients with ANCA-associated vasculitis and rheumatoid arthritis when compared to the healthy population [79 , 83 ].

Upon priming of neutrophils by tumor necrosis factor {alpha} (TNF-{alpha}) as may occur during a viral or bacterial infection and subsequent to activation by fMLP or IL-8 most of the released PR3 is expressed on the plasma membrane, whereas HLE and MPO are partly expressed on the membrane and mainly released into the extracellular medium [76 , 80 ].

The way PR3 is associated with the plasma membrane and the functional significance of membrane-associated PR3 are still under investigation. The interaction between PR3 and the plasma membrane does not seem to result from charge interactions [76 ], whereas binding of HLE or CatG is largely charge dependent [84 ]. Membrane PR3 interaction does not depend on membrane sialic acid residues, nor is PR3 anchored to the plasma membrane via a GPI-link [76 ]. Membrane-associated PR3 appears as a 29-kDa band on SDS-PAGE gels [76 ] and can still bind to {alpha}1-antitrypsin ({alpha}1-AT or {alpha}1 protease inhibitor, {alpha}1-PI) [85 ]. This rules out the possibility that PR3, complexed to {alpha}1-AT, is bound to the serine proteinase inhibitor (Serpin) enzyme complex (SEC)-receptor, as earlier proposed [86 ]. The association of PR3 with the plasma membrane seems to be covalent [76 ]. However, association of PR3 to the membrane also has been described through lipid interactions, in contrast to that of HLE and MPO [87 ]. This lipid-associated PR3 is still enzymatically active, as has also been shown for HLE and CatG [84 ]. This excludes the possibility that the secreted pro-form of PR3, which is enzymatically inactive, is bound to the plasma membrane. Only recently a specific membrane molecule on endothelial cells has been described that interacts with PR3 [88 ]. The same molecule is possibly responsible for the membrane association of PR3 on neutrophils. Such a receptor on neutrophils has been reported for HLE [89 , 90 ].

Differences in expression between PR3, HLE, CatG, and MPO are summarized in Table 3 . In summary, PR3, in contrast to HLE and MPO, is expressed on the plasma membrane of resting neutrophils. It has even been shown that the occurrence of a high percentage of neutrophils expressing mPR3 is a risk factor for vasculitis. This suggests that PR3 expression on the plasma membrane of neutrophils is clinically relevant and might favor the occurrence of chronic inflammation.

PR3 expression in non-myeloid cells
Whether endothelial cells express PR3 is still a matter of debate. Mayet et al described that endothelial cells and a number of other non-myeloid cells express PR3 after stimulation with proinflammatory cytokines [91 , 92 ]. This PR3 was suggested to be synthesized de novo [91 , 93 ], but the production of PR3 mRNA was transient [94 ]. Although Sibelius et al. [94 ] have confirmed PR3 expression on endothelial cells, other groups could not confirm the presence of this protein nor mRNA expression of PR3 in cytokine-stimulated endothelial cells [88 , 95 , 96 ]. If endothelial cells produce PR3 PR3-ANCA can bind directly to PR3 expressed on endothelial cells, recruit neutrophils and monocytes via complement activation, and cause damage to the vessel wall. This would give an explanation for the vasculitis and glomerulonephritis seen in WG.

It is interesting that PR3 and MPO themselves can bind to endothelial cells in vitro [97 , 98 ]. Only recently a membrane molecule on endothelial cells has been identified that specifically binds PR3 [88 ]. In addition, endothelial cells could internalize PR3 and MPO, whereas only MPO could also be internalized by epithelial cells [99 ]. These recent data emphasize the fact that PR3 can also have a specific interaction with endothelial cells.

The expression of PR3 by non-myeloid cells is difficult to explain considering that one of the transcription factors, PU.1, that is necessary for the transcription of PR3, is expressed in myeloid cells and B cells only. One explanation could be that in endothelial cells another nuclear protein resembling PU.1 binds to the PR3 promoter region inducing transient expression of the PR3 gene. Another explanation could be that the transcription of PR3 is leaky. This is unlikely because PR3 is an active protease and if expressed in an environment not equipped to store this protease, PR3 would easily degrade other proteins.


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FUNCTIONS OF PR3
 
PR3 is one of the four neutral serine proteases in neutrophils and monocytes and has large homology with the other neutrophil and monocyte serine proteases HLE and CatG [2 , 32 ]. The active site of PR3 is very similar to that of HLE and CatG [100 ]. So, many of the physiological functions of PR3 that are dependent on its enzymatic activity will overlap with the function of HLE and CatG. However, PR3 also has functions distinct from HLE and CatG. PR3 is an important protein in WG and myeloid leukemia, and has a whole array of physiological and, possibly, pathophysiological functions.

Regulation of myeloid differentiation by PR3
Several data support the possible role for PR3 in growth and differentiation of granulocytes and monocytes (shown in a hypothetical scheme in Figure 4 ). In hematopoietic progenitor cells PR3 expression is up-regulated by granulocyte colony-stimulating factor (G-CSF) as the PR3 gene was shown to be a G-CSF-responsive gene [101 ]. This G-CSF-induced PR3 expression is dependent on the PU.1, C/EBP, and c-Myb binding sites in the PR3 promoter region. The transcription factor PU.1 played a major role in inducing this expression of PR3. Constitutive overexpression of the active form of PR3 induced factor-independent growth of hematopoietic progenitor cells expressing the G-CSF receptor [101 ]. So, in the early steps of myeloid differentiation up-regulation of PR3 causes growth of progenitor cells (Fig. 4 , part 1). Later during myeloid differentiation, after the promyelocytic stage, PR3 expression is down-regulated and growth arrest and further differentiation along the granulocytic lineage is induced [12 ] (Fig. 4 , part 4). During synthesis of PR3 at the promyelocytic stage small amounts of the pro-form of PR3 escape granular targeting and are secreted [63 , 64 ]. This secreted pro-form can reduce the fraction of granulocyte and monocyte colony-forming units (CFU-GM) in S-phase of hematopoietic progenitor cells, which implies a function for PR3 as a putative feedback regulator of myeloid differentiation (Fig. 4 , part 2). It is interesting that this feedback regulation by PR3 is reversible and abrogated by G-CSF and GM-CSF [75 ]. Furthermore, during the promyelocytic stage, PR3 can exert certain functions that can regulate cell differentiation at this stage [102 103 104 ]. At the promyelocytic stage it was shown that PR3 can truncate the nuclear factor NF-{kappa}B subunit [102 ], degrade the 28-kDa heat shock protein, which is a potential component of signal transduction pathways [103 ], and truncate the Sp1 transcription factor [104 ] (Fig. 4 , part 3). Decrease of the degradation of these proteins upon down-regulation of PR3 might provide a mechanism through which differentiating promyeloid cells can acquire a new repertoire of gene expression. Of the above-mentioned functions of PR3 in myeloid differentiation only the truncation of the NF-{kappa}B subunit could also be caused by CatG or HLE [102 ].



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  		Figure 4. Role of PR3 in the myeloid differentiation outlined in a hypothetical scheme. Shown in boxes are the functions of PR3 with references. CD34-positive hematopoietic progenitors cells derived from the bone marrow differentiate to myeloid progenitor precursor cells upon culture with IL-3, granulocyte (G), or granulocyte-monocyte (GM) colony-stimulating factor (CSF). Factor-independent growth of these hematopoietic progenitor cells is induced by up-regulation of PR3 by G-CSF (1). This induction of growth is dependent on the expression of the G-CSF receptor and the enzymatic activity of PR3. Myeloid progenitor cells differentiate through the myelomonocytic progenitor and myeloblast stage into promyelocytic cells (like HL60), which have the highest expression of PR3 mRNA, and thus production of most of the PR3 protein occurs during this stage of myeloid differentiation. A small part of PR3 is synthesized as an inactive pro-form. Secretion of this pro-form can reduce the fraction of granulocyte-monocyte colony-forming units (CFU-GM) in S-phase and thus have a direct effect on normal hematopoietic progenitor cells (2). So, PR3 can form a feedback loop in myeloid differentiation. G-CSF and GM-CSF counteract this effect of PR3. PR3 expressed by promyelocytic cells can have a direct effect on cell differentiation (3). Promyelocytic cells go into growth arrest and further differentiate into mature neutrophils once PR3 is down-regulated (4).

Although PR3 is not the sole agent that controls myeloid differentiation, the role for PR3 in myeloid differentiation is thus far unique for neutrophil- and monocyte-derived serine proteases as it has not been described nor proposed for other neutrophil and monocyte derived serine proteases (summarized in Table 4 ). This role as a feedback regulator in myeloid differentiation might implicate PR3 in the pathogenesis of myeloid leukemia as well as in WG. The disturbances in maturation and granule formation that characterize myeloid leukemia could lead to increased secretion of PR3 and thereby contribute to the suppression of normal myeloid differentiation. A defect in the down-regulation of PR3 could, thus, induce uncontrolled growth of promyelocytic cells as seen in myeloid leukemia. In WG PR3 might contribute to inflammation by enhanced myeloid differentiation caused by enhanced down-regulation of PR3 [105 ].


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  		Table 4. Differences in Function in Myeloid Differentiation, Physiological Function, and Role in Apoptosis Induction Between PR3, HLE, and CatG

Physiological functions of PR3
One of the physiological roles ascribed to PR3 and the other neutrophil- and monocyte-derived serine proteases is killing of phagocytosed microbes. PR3 has greatest microbicidal activity against gram-negative bacteria (like Escherichia coli) but can also kill gram-positive bacteria (like S. faecalis) and fungi (like Candida albicans) [11 , 81 ]. The microbicidal activity of serine proteases is independent of their enzymatic activity and involves inhibition of synthesis of macromolecules, energy-dependent membrane transport, and inhibition of oxygen metabolism of bacteria. The microbicidal activity of serine proteases probably operates through charge interactions between the serine protease and the bacterial membrane [106 ]. Thus far, only for CatG and AZU specific peptides have been identified that account for this bactericidal activity [107 , 108 ].

Another physiological role ascribed to PR3 and HLE is migration of neutrophils through the basement membranes. PR3 has an elastase-like enzymatic activity and can degrade a variety of extracellular matrix proteins and basement membrane proteins like elastin [9 , 81 , 109 ], fibrinogen and proteoglycans [110 ], fibronectin, laminin, vitronectin, and collagen type IV [2 ]. PR3 can also degrade casein and hemoglobin [81 ].

Enzymatically active PR3 has been implicated in the modulation of inflammatory mediators. PR3, and not HLE or CatG, is involved in the cleavage and inactivation of C1 inhibitor [111 ]. Furthermore, PR3 as well as HLE can cleave membrane-bound TNF-{alpha} [112 , 113 ], IL-1ß [113 ], and the IL-2 receptor [114 ]. Whether these cleaved products of TNF-{alpha} and IL-1ß are biologically active has still to be determined. PR3, HLE, and CatG are able to degrade and inactivate IL-6 [115 ] as well as activate latent transforming growth factor ß (TGF-ß). However, PR3 is most potent in this activation of TGF-ß [116 ]. Only cleavage of IL-8 to a biologically more active form has thus far been described for PR3 only [117 ].

PR3, HLE, and CatG have been implicated in modulating the activity of platelets and endothelial cells [118 , 119 ], possibly by cleavage and subsequent inactivation of proteinase-activated receptors (PAR). PR3 and HLE are able to potentiate the CatG-induced platelet activation [118 ]. PR3 and HLE can cleave PAR on platelets and endothelial cells downstream of the thrombin cleavage site, thus disabling the activation of these receptors by thrombin [120 ], indicating that PR3 and HLE can inhibit the biological actions of thrombin. Finally, PR3 can inhibit the activation of neutrophil NADPH-oxidase. It is interesting that this inhibition was independent of the enzymatic activity of PR3 [121 ].

Of the above-mentioned physiological functions of PR3 cleavage of IL-8 and C1 inhibitor and inhibition of NADPH-oxidase have thus far been described for PR3 only (Table 4) . Granulocyte activation as seen in WG and subsequent degranulation may locally increase PR3 levels, resulting in cleavage of C1 inhibitor and IL-8. Degradation of C1 inhibitor could possibly lead to further activation of the complement pathway at sites of neutrophil infiltration causing more neutrophil migration, activation, and tissue damage. Cleavage of IL-8 to a biologically more active form can amplify the chemotactic activity of IL-8 and further enhance neutrophil recruitment to sites of inflammation, which could possibly lead to more tissue damage. Modulation of cytokines by neutrophil- and monocyte-derived serine proteases might be important for the cytokine balance at local foci of inflammation where the physiological inhibitors of proteases are not abundantly present.

PR3 and endothelium
Systemic vasculitis affecting small blood vessels and pauci-immune necrotizing crescentic glomerulonephritis are the major features of WG [13 ]. Several in vitro studies have provided evidence that PR3 may directly contribute to this vascular injury. PR3 as well as MPO can bind to human umbilical vein endothelial cells (HUVEC) in vitro. Anti-PR3 or anti-MPO antibodies [97 , 98 , 122 ] can still recognize PR3 and MPO bound to HUVEC, respectively. Binding of PR3 to HUVEC could be inhibited by {alpha}1-AT [97 ]. PR3, HLE, and CatG can induce detachment and cytolysis of HUVEC, which was dependent on their enzymatic activity [123 ]. Furthermore, PR3 and HLE but not CatG could enhance IL-8 production of HUVEC in vitro. The induction of IL-8 production by PR3 was independent of its enzymatic activity, whereas that by HLE was dependent on the enzymatic activity [124 ]. Recently, it was shown that PR3 can also induce MCP-1 production of HUVEC in vitro [125 ]. Finally, PR3 and HLE can induce apoptosis of human endothelial cells [126 , 127 ]. Only recently it was shown that an enzymatically inactive carboxy-terminal domain of PR3 was responsible for apoptosis induction [128 ]. The above-mentioned activities of PR3 on endothelial cells might be receptor mediated as, only recently, a membrane molecule on endothelial cells that interacts with PR3 has been identified [88 ]. This supports data showing that PR3, both enzymatically active and inactive, binds to and enters human endothelial cells and induces apoptosis [99 ].

So, PR3, once released, could activate endothelial cells and contribute to the perpetuation of the inflammatory process in systemic vasculitis by enhancing IL-8 and MCP-1 production with subsequent recruitment of neutrophils, monocytes, and T cells. Furthermore, released PR3 can bind to endothelial cells, be internalized, and induce apoptosis of endothelial cells, which may result in vascular damage.

Inhibitors of PR3
PR3, HLE, and CatG are strong proteolytic enzymes, and the activity of these proteases is precisely regulated by endogenous protein inhibitors called serpins (serine protease inhibitors; Table 5 ). The main physiological inhibitor for PR3 as well as HLE is {alpha}1-antitrypsin ({alpha}1-AT or {alpha}1-protease inhibitor) [2 , 129 ], whereas the physiological inhibitor of CatG is {alpha}1-antichymotrypsin [2 ]. PR3 and HLE were also inhibited by elafin [130 ], a human skin-derived inhibitor, and to a lesser extent by {alpha}2-macroglobulin [2 , 129 ]. In contrast to HLE and CatG, PR3 is not inhibited by secretory leukoprotease inhibitor (SLPI) and is only weakly inhibited by eglin c [2 ]. HLE is inhibited by glycosaminoglycans independent of the substrate, whereas PR3 activity to large substrates like elastin, but not to small substrates, is partially inhibited by glycosaminoglycans [131 ]. Only recently it was shown that DNase partially inhibited the enzymatic activity of HLE and CatG but had no effect on the enzymatic activity of PR3 [132 ].


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  		Table 5. Interaction of PR3, HLE, and CatG with natural inhibitors

PR3 complexed to {alpha}1-AT has been found in plasma of WG patients and healthy controls, although free PR3 could also be detected [133 , 134 ]. Under normal conditions the activity of PR3 and HLE is tightly regulated by a large excess of circulating anti-proteases like {alpha}1-AT. The {alpha}1-AT is encoded by a highly polymorphic gene, with more than 75 alleles, defining severely (Z allel), medium, and non-deficient (M allel) {alpha}1-AT phenotypes [reviewed in ref. 135 ]. Certain variants of {alpha}1-AT may bind and inactivate PR3 to a lesser extent, thus influencing the balance between protease and anti-protease at the site of inflammation. Several groups have described that PR3-ANCA-positive vasculitis is more common in patients with the deficient ZZ phenotype [136 137 138 139 140 ]. Abnormal {alpha}1-AT phenotypes are associated with an increased risk of WG as well as with increased morbidity [141 , 142 ]. These severe {alpha}1-AT deficiencies are not specific for patients with antibodies to PR3 because they have also been described as a risk factor for the development of emphysema [135 ], various hepatic disorders, and several autoimmune diseases, among which are uveitis and systemic lupus erythematosus [reviewed in refs. 143 144 ].

Apart from the genetically determined imbalance between PR3 or HLE and {alpha}1-AT an acquired imbalance between PR3 or HLE and {alpha}1-AT seems a factor that influences activity of PR3 or HLE. Under pathological conditions {alpha}1-AT can be degraded and inactivated by a number of proteins released from activated neutrophils like HLE [145 , 146 ], metalloproteinases [147 ], and reactive oxygen species [148 ], thus increasing the local activity of released PR3 and HLE. Furthermore, oxidation of {alpha}1-AT by oxygen radicals reduces the association of {alpha}1-AT with HLE [149 ]. In patients with WG PR3-ANCA can interfere with the inhibition of PR3 by {alpha}1-AT [150 , 151 ]. Inactivation or low serum levels of {alpha}1-AT may cause PR3 and HLE to escape from their physiological inhibitor, resulting in tissue destruction [152 ]. The genetically determined or acquired deficiency of {alpha}1-AT influences both the activity of PR3 and HLE, and thus may be a risk factor for patients with WG. However, this {alpha}1-AT deficiency seems not to account for the specific development of autoreactivity to PR3 because it does not distinguish between PR3 and HLE.

One important issue is that PR3, in contrast to HLE, is not inhibited by SLPI (Table 5) . SLPI is present in large amounts in respiratory epithelial lining fluid and may play a significant role in protecting the normal respiratory epithelium, especially in the upper airways, where levels of SLPI are highest. Because PR3 is not inactivated by SLPI PR3 may play a significant role in protease-mediated airway damage, and may thus be a risk factor for patients with WG are for chronic obstructive pulmonary diseases.

In sputum of patients with cystic fibrosis higher levels of PR3 than HLE were found compared to patients with chronic bronchitis without cystic fibrosis. PR3 in sputum appeared as a free enzymatically active enzyme or complexed to inhibitors like {alpha}1-AT. The clinical relevance of high amounts of PR3 in the sputum is illustrated by its correlation with the severity of cystic fibrosis, whereas the latter did not correlate with HLE levels [153 ]. PR3 as well as HLE can trigger airway gland secretion [153 ] and can induce emphysema in hamsters upon intratracheal administration [9 ]. Pulmonary active WG patients did not have an elevated level of free PR3 in their bronchoalveolar lavage fluid and, in contrast, mainly PR3/{alpha}1-AT complexes were found [154 ]. Therefore it is likely that {alpha}1-AT is the primary physiologically relevant inhibitor protecting the lower respiratory tract against PR3 and HLE.

Consequently, damage to lung tissue can result from, on the one hand, prolonged exposure to serine proteases like PR3 and HLE as in chronic inflammation and, on the other hand, from an insufficiency of appropriate inhibitors as in the case of genetically determined or acquired deficiency of {alpha}1-AT. So, the protease/anti-protease imbalance is a general contributor to the diverse conditions that result in chronic pulmonary inflammation. The local ratio of PR3 and HLE and antiproteases may determine the final proteolytic damage by neutrophils and monocytes.


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CONCLUSION
 
Proteinase 3 (PR3) is one of the four serine protease homologues [1 ] that are localized in the azurophilic granules of neutrophils and the granules of monocytes [2 3 4 ]. PR3 differs from the other serine proteases as PR3 has been implicated as autoantigen in Wegener’s granulomatosis and as target for immunotherapy in myeloid leukemia. Reviewing current literature we conclude that PR3 differs from the other serine protease homologs by a whole array of physiological and, possibly, pathophysiological functions, as summarized below.

At the level of gene localization and gene regulation PR3, HLE, and CatG are not very polymorphic proteins. Only minor variability is seen in the PR3 sequence (Table 1) . Whether this variability can account for differences at the protein level is still unknown. However, the polymorphism of PR3 cannot account for alloresponsiveness of donor lymphocytes against recipient leukemic cells. Furthermore, most regulatory elements in the promoter region of PR3 are common for the neutrophil-derived serine proteases. Nonetheless, three regulatory elements present in the promoter regions of HLE or CatG are not present in the promoter region of PR3 (Table 2) . Whether these differences can account for a possible aberrant expression of PR3 in patients with WG or myeloid leukemia still has to be determined.

The processing of PR3 is very similar to that of other neutrophil-derived serine proteases, but major differences are seen in the expression and storage of PR3. PR3 is, apart from its presence in azurophilic granules, also present in the secretory vesicles and specific granules of neutrophils and monocytes, and PR3 is expressed on the plasma membrane of resting neutrophils (Table 3) . It is intriguing that this membrane expression is bimodal and that the presence of a high percentage of neutrophils with PR3 membrane expression seems to be a risk factor for vasculitis.

The physiological functions of PR3 that depend on its enzymatic activity are very similar for PR3, HLE, and CatG because all three proteins are serine proteases. Modulation of inflammatory mediators has been described for PR3, HLE and CatG, but cleavage of IL-8 and C1 inhibitor and inhibition of NADPH-oxidase has thus far been described for PR3 only (Table 4) . One major difference in function between neutrophil-derived serine proteases is the unique role PR3 may play as a feedback regulator in myeloid differentiation. Furthermore, PR3, both enzymatically active and inactive, binds to and enters human endothelial cells and induces apoptosis. These activities of PR3 on endothelial cells may be receptor mediated.

A final difference between the serine proteases relates to their inhibition by natural inhibitors. Most of the inhibitors of HLE or CatG can also inhibit the enzymatic activity of PR3 (Table 5) with the exception of SLPI, which does inhibit HLE and CatG but does not inhibit PR3.

What is the significance of the above-summarized differences between PR3 and the other serine protease homologs for our understanding of the role of PR3 as autoantigen in WG or as target for immunotherapy in myeloid leukemias?

For our understanding of the role of PR3 in the pathogenesis of WG four of the above-mentioned differences may be of relevance. First, the role of PR3 as a feedback regulator in myeloid differentiation might be relevant as a defect in the down-regulation of PR3 at the promyelocytic stage (Fig. 4 , part 4) may cause enhanced myeloid differentiation, which may lead to enhanced inflammation. Second, PR3, both enzymatically active and inactive, binds to and enters human endothelial cells that could be relevant for the inflammatory potential of PR3 in WG. PR3 can bind to endothelial cells, activate these cells and induce apoptosis of endothelial cells, with damage to the vessel wall. The latter two factors define PR3 as a protein with high inflammatory potential. It is possible that autoimmunity to PR3 is induced in an inflammatory milieu where PR3 is more immunogenic. Also, an aberrant clearance of PR3 and improper inhibition of PR3 can enhance the inflammatory potential of PR3. Third, upon activation of neutrophils PR3 is readily secreted from the secretory vesicles and can cause tissue damage when not properly inhibited. Furthermore, the occurrence of a high percentage of neutrophils expressing PR3 on their membrane shown to be a risk factor for vasculitis, might favor the occurrence of chronic inflammation. This bimodal expression of PR3 might be genetically controlled. Whether this bimodal expression of PR3 can be accounted for by a bi-allelic restriction fragment length polymorphism described in the PR3 locus has still to be determined. The interaction of this membrane-associated PR3 with PR3-ANCA might be important for the pathophysiology of WG. Finally, aberrant expression of PR3, due to polymorphisms in the amino acid sequence or variants in the promoter region might be important for the induction of autoantibodies to PR3.

For our understanding of the role of PR3 in the development of leukemia or as target for immunotherapy in myeloid leukemias the role of PR3 as a feedback regulator in myeloid differentiation may be of relevance. A defect in the down-regulation of PR3 during the promyelocytic stage of differentiation (Fig. 4 , part 4) could lead to increased secretion of PR3 and thereby contribute to the suppression of normal myeloid differentiation via the secreted pro-form of PR3 (Fig.4 , part 2). The factor-independent growth of hematopoietic progenitors cells induced by PR3 could represent one of the early stages in the development of leukemia (Fig. 4 , part 1). So, overexpression of PR3 could lead to uncontrolled growth of myeloid cells as seen in leukemia. In contrast, in myeloid leukemias PR3 is often overexpressed. Overexpressed PR3 can be processed and presented in MHC class I molecules that might induce CTLs specific for PR3 peptides. These CTLs specific for peptides derived from PR3 have been shown to preferentially lyse myeloid leukemia cells and inhibit granulocyte-macrophage colony forming unit activity, which could be used in leukemia-specific adoptive immunotherapy.

In conclusion, PR3 is a very intriguing protein with a large array of physiological functions. More research on these physiological functions of PR3 can give more insight into the role PR3 may play in the pathophysiology of WG and myeloid leukemia.

Received September 6, 2000; revised September 30, 2000; accepted October 3, 2000.


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