NB1 mediates surface expression of the ANCA antigen proteinase 3 on human neutrophils

Vietinghoff, Sibylle von; Tünnemann, Gisela; Eulenberg, C.; Wellner, Maren; Cardoso, M. Cristina; Luft, Friedrich C.; Kettritz, Ralph

doi:10.1182/blood-2006-10-055327

Cited by 117 publications

(120 citation statements)

References 42 publications

(46 reference statements)

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“…However, it is noteworthy that the membrane protein CD177, reported to be a protein that can associate with PR3 at the neutrophil plasma membrane, was not upregulated on apoptosis and was not part of this complex in RBL cells. Nonetheless, it was confirmed in this study that exogenous purified PR3 can specifically bind to CD177 expressed on resting RBL/CD177 cells, whereas no PR3 binding was observed on wild type RBL cells (data not shown), thus confirming earlier results (23,24) showing that CD177 is a receptor for exogenous PR3.…”

Section: Discussionsupporting

confidence: 80%

“…In neutrophils, PR3 is expressed on the same neutrophil subset as CD177 (also called NB1) (23,24), a GPI-anchored glycoprotein. CD177 has been suggested to be a PR3 "receptor" involved in PR3 constitutive membrane expression in neutrophils, and we hypothesized that the lack of constitutive PR3 membrane expression of RBL/PR3 cells could be due to the absence of CD177 expression in these cells.…”

Section: Cd177 Is Not Associated With Membrane Pr3 On Apoptosismentioning

confidence: 99%

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Proteinase 3, the Autoantigen in Granulomatosis with Polyangiitis, Associates with Calreticulin on Apoptotic Neutrophils, Impairs Macrophage Phagocytosis, and Promotes Inflammation

Gabillet

Millet

Pederzoli-Ribeil

et al. 2012

The Journal of Immunology

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Proteinase 3 (PR3) is the target of anti-neutrophil cytoplasm Abs in granulomatosis with polyangiitis, a form of systemic vasculitis. Upon neutrophil apoptosis, PR3 is coexternalized with phosphatidylserine and impaired macrophage phagocytosis. Calreticulin (CRT), a protein involved in apoptotic cell recognition, was found to be a new PR3 partner coexpressed with PR3 on the neutrophil plasma membrane during apoptosis, but not after degranulation. The association between PR3 and CRT was demonstrated in neutrophils by confocal microscopy and coimmunoprecipitation. Evidence for a direct interaction between PR3 and the globular domain of CRT, but not with its P domain, was provided by surface plasmon resonance spectroscopy. Phagocytosis of apoptotic neutrophils from healthy donors was decreased after blocking lipoprotein receptor-related protein (LRP), a CRT receptor on macrophages. In contrast, neutrophils from patients with granulomatosis with polyangiitis expressing high membrane PR3 levels showed a lower rate of phagocytosis than those from healthy controls not affected by anti-LRP, suggesting that the LRP-CRT pathway was disturbed by PR3-CRT association. Moreover, phagocytosis of apoptotic PR3-expressing cells potentiated proinflammatory cytokine in vitro by human monocyte-derived macrophages and in vivo by resident murine peritoneal macrophages, and diverted the anti-inflammatory response triggered by the phagocytosis of apoptotic cells after LPS challenge in thioglycolate-elicited murine macrophages. Therefore, membrane PR3 expressed on apoptotic neutrophils might amplify inflammation and promote autoimmunity by affecting the anti-inflammatory “reprogramming” of macrophages.

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Section: Discussionsupporting

confidence: 80%

Section: Cd177 Is Not Associated With Membrane Pr3 On Apoptosismentioning

confidence: 99%

Proteinase 3, the Autoantigen in Granulomatosis with Polyangiitis, Associates with Calreticulin on Apoptotic Neutrophils, Impairs Macrophage Phagocytosis, and Promotes Inflammation

Gabillet

Millet

Pederzoli-Ribeil

et al. 2012

The Journal of Immunology

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“…Molecular modeling and surface plasmon resonance demonstrated that PR3 can bind directly and robustly to the plasma membrane as well as lipid vesicles, and this binding occurs with a significantly higher affinity than HNE (27). Previously studies have shown that PR3 is expressed at the membrane of resting neutrophils through its ability to bind to CD177 (39,40). However, this type of interaction does not appear to play a role in apoptosis-induced membrane expression of PR3, which is independent of CD177 expression (11).…”

Section: Discussionmentioning

confidence: 95%

Proteinase 3 Is a Phosphatidylserine-binding Protein That Affects the Production and Function of Microvesicles

Martin¹,

Kantari‐Mimoun²,

Yin³

et al. 2016

Journal of Biological Chemistry

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Proteinase 3 (PR3), the autoantigen in granulomatosis with polyangiitis, is expressed at the plasma membrane of resting neutrophils, and this membrane expression increases during both activation and apoptosis. Using surface plasmon resonance and protein-lipid overlay assays, this study demonstrates that PR3 is a phosphatidylserine-binding protein and this interaction is dependent on the hydrophobic patch responsible for membrane anchorage. Molecular simulations suggest that PR3 interacts with phosphatidylserine via a small number of amino acids, which engage in long lasting interactions with the lipid heads. As phosphatidylserine is a major component of microvesicles (MVs), this study also examined the consequences of this interaction on MV production and function. PR3-expressing cells produced significantly fewer MVs during both activation and apoptosis, and this reduction was dependent on the ability of PR3 to associate with the membrane as mutating the hydrophobic patch restored MV production. Functionally, activation-evoked MVs from PR3-expressing cells induced a significantly larger respiratory burst in human neutrophils compared with control MVs. Conversely, MVs generated during apoptosis inhibited the basal respiratory burst in human neutrophils, and those generated from PR3-expressing cells hampered this inhibition. Given that membrane expression of PR3 is increased in patients with granulomatosis with polyangiitis, MVs generated from neutrophils expressing membrane PR3

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“…Although the vast majority of PR3 is stored intracellularly in primary granules together with other proteases, small amounts of PR3 prestored in as yet poorly characterized small vesicles are rapidly mobilized during priming. This small fraction of PR3 is externalized together with NB1 (CD177), a glycolipid-anchored membrane protein (5,6), and is presented on the neutrophil surface as a complex with NB1 (7). Simultaneous interaction of cANCAs with membrane-bound PR3 and FcgR is believed to trigger full activation and premature degranulation of extravasating neutrophils around small vessels in patients with active disease (3).…”

Section: W Egener's Granulomatosis (Wg) Is An Autoimmunementioning

confidence: 99%

Mapping of Conformational Epitopes on Human Proteinase 3, the Autoantigen of Wegener’s Granulomatosis

Kuhl

Korkmaz

Utecht³

et al. 2010

The Journal of Immunology

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Anti-neutrophil cytoplasmic Abs (cANCAs) against conformational epitopes of proteinase 3 (PR3) are regarded as an important pathogenic marker in Wegener’s granulomatosis (WG). Although the three-dimensional structure of PR3 is known, binding sites of mAbs and cANCAs have not been mapped to date. Competitive binding and biosensor experiments suggested the existence of four nonoverlapping areas on the PR3 surface. In this paper, we present an approach to identify these discontinuous surface regions that cannot be mimicked by linear peptides. The very few surface substitutions found in closely related PR3 homologs from primates, which were further varied by the construction of functional human-gibbon hybrids, resulted in the differential loss of three Ab binding sites, two of which were mapped to the N-terminal β-barrel and one to the linker segment connecting the N- and C-terminal barrels of PR3. The sera from WG patients differed in their binding to gibbon PR3 and the gibbon-human PR3 hybrid, and could be divided into two groups with similar or significantly reduced binding to gibbon PR3. Binding of almost all sera to PR3–α1-protease inhibitor (α1–PI) complexes was even more reduced and often absent, indicating that major antigenic determinants overlap with the active site surface on PR3 that associates with α1-PI. Similarly, the mouse mAbs CLB12.8 and 6A6 also did not react with gibbon PR3 and PR3–α1-PI complexes. Our data strongly suggest that cANCAs from WG patients at least in part recognize similar surface structures as do mouse mAbs and compete with the binding of α1-PI to PR3.

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NB1 mediates surface expression of the ANCA antigen proteinase 3 on human neutrophils

Cited by 117 publications

References 42 publications

Proteinase 3, the Autoantigen in Granulomatosis with Polyangiitis, Associates with Calreticulin on Apoptotic Neutrophils, Impairs Macrophage Phagocytosis, and Promotes Inflammation

Proteinase 3, the Autoantigen in Granulomatosis with Polyangiitis, Associates with Calreticulin on Apoptotic Neutrophils, Impairs Macrophage Phagocytosis, and Promotes Inflammation

Proteinase 3 Is a Phosphatidylserine-binding Protein That Affects the Production and Function of Microvesicles

Mapping of Conformational Epitopes on Human Proteinase 3, the Autoantigen of Wegener’s Granulomatosis

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