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• W2149257023 abstract "The glycosylphosphatidylinositol (GPI)-anchored neutrophil-specific receptor NB1 (CD177) presents the autoantigen proteinase 3 (PR3) on the membrane of a neutrophil subset. PR3-ANCA-activated neutrophils participate in small-vessel vasculitis. Since NB1 lacks an intracellular domain, we characterized components of the NB1 signaling complex that are pivotal for neutrophil activation. PR3-ANCA resulted in degranulation and superoxide production in the mNB1pos/PR3high neutrophils, but not in the mNB1neg/PR3low subset, whereas MPO-ANCA and fMLP caused similar responses. The NB1 signaling complex that was precipitated from plasma membranes contained the transmembrane receptor Mac-1 (CD11b/CD18) as shown by MS/MS analysis and immunoblotting. NB1 co-precipitation was less for CD11a and not detectable for CD11c. NB1 showed direct protein-protein interactions with both CD11b and CD11a by surface plasmon resonance analysis (SPR). However, when these integrins were presented as heterodimeric transmembrane proteins on transfected cells, only CD11b/CD18 (Mac-1)-transfected cells adhered to immobilized NB1 protein. This adhesion was inhibited by mAb against NB1, CD11b, and CD18. NB1, PR3, and Mac-1 were located within lipid rafts. In addition, confocal microscopy showed the strongest NB1 co-localization with CD11b and CD18 on the neutrophil. Stimulation with NB1-activating mAb triggered degranulation and superoxide production in mNB1pos/mPR3high neutrophils, and this effect was reduced using blocking antibodies to CD11b. CD11b blockade also inhibited PR3-ANCA-induced neutrophil activation, even when β2-integrin ligand-dependent signals were omitted. We establish the pivotal role of the NB1-Mac-1 receptor interaction for PR3-ANCA-mediated neutrophil activation. The glycosylphosphatidylinositol (GPI)-anchored neutrophil-specific receptor NB1 (CD177) presents the autoantigen proteinase 3 (PR3) on the membrane of a neutrophil subset. PR3-ANCA-activated neutrophils participate in small-vessel vasculitis. Since NB1 lacks an intracellular domain, we characterized components of the NB1 signaling complex that are pivotal for neutrophil activation. PR3-ANCA resulted in degranulation and superoxide production in the mNB1pos/PR3high neutrophils, but not in the mNB1neg/PR3low subset, whereas MPO-ANCA and fMLP caused similar responses. The NB1 signaling complex that was precipitated from plasma membranes contained the transmembrane receptor Mac-1 (CD11b/CD18) as shown by MS/MS analysis and immunoblotting. NB1 co-precipitation was less for CD11a and not detectable for CD11c. NB1 showed direct protein-protein interactions with both CD11b and CD11a by surface plasmon resonance analysis (SPR). However, when these integrins were presented as heterodimeric transmembrane proteins on transfected cells, only CD11b/CD18 (Mac-1)-transfected cells adhered to immobilized NB1 protein. This adhesion was inhibited by mAb against NB1, CD11b, and CD18. NB1, PR3, and Mac-1 were located within lipid rafts. In addition, confocal microscopy showed the strongest NB1 co-localization with CD11b and CD18 on the neutrophil. Stimulation with NB1-activating mAb triggered degranulation and superoxide production in mNB1pos/mPR3high neutrophils, and this effect was reduced using blocking antibodies to CD11b. CD11b blockade also inhibited PR3-ANCA-induced neutrophil activation, even when β2-integrin ligand-dependent signals were omitted. We establish the pivotal role of the NB1-Mac-1 receptor interaction for PR3-ANCA-mediated neutrophil activation. IntroductionAnti-neutrophil cytoplasmic auto-antibodies (ANCA) 2The abbreviations used are: ANCA, anti-neutrophil cytoplasmic auto-antibodies; GPI, glycosylphosphatidylinositol; fMLP, f-met-leu-phe; PMA, phorbol-2-myristate-13-acetate; DHR, 2.2′-azino-bis (3-ethylbenzthiazoline-6-sulfonicacid), dihydrorhodsamine; DFP, diisopropylfluorophosphate. are found in patients with Wegener granulomatosis, microscopic polyangitis, Churg-Strauss syndrome, and necrotizing crescentic glomerulonephritis (1van 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. Hauu The T. Lancet. 1985; i: 425-429Abstract Scopus (1395) Google Scholar, 2Falk R.J. Jennette J.C. N. Engl. J. Med. 1988; 318: 1651-1657Crossref PubMed Scopus (1227) Google Scholar). PR3- and MPO-ANCA binding to their target antigens on the membrane of neutrophils and monocytes leads to cell activation (3Falk R.J. Terrell R.S. Charles L.A. Jennette J.C. Proc. Natl. Acad. Sci. U.S.A. 1990; 87: 4115-4119Crossref PubMed Scopus (1100) Google Scholar, 4Savage C.O. Pottinger B.E. Gaskin G. Pusey C.D. Pearson J.D. Am. J. Pathol. 1992; 141: 335-342PubMed Google Scholar). ANCA pathogenicity and the pivotal role of the ANCA-neutrophil interaction were established in several animal models (5Xiao H. Heeringa P. Hu P. Liu Z. Zhao M. Aratani Y. Maeda N. Falk R.J. Jennette J.C. J. Clin. Invest. 2002; 110: 955-963Crossref PubMed Scopus (986) Google Scholar, 6Pfister H. Ollert M. Froehlich L.F. Quantanilla-Martinez L. Colby T.V. Specks U. Jenne D. Blood. 2004; 104: 1411-1418Crossref PubMed Scopus (218) Google Scholar, 7Little M.A. Smyth C.L. Yadav R. Ambrose L. Cook H.T. Nourshargh S. Pusey C.D. Blood. 2005; 106: 2050-2058Crossref PubMed Scopus (238) Google Scholar, 8Xiao H. Heeringa P. Liu Z. Huugen D. Hu P. Maeda N. Falk R.J. Jennette J.C. Am. J. Pathol. 2005; 167: 39-45Abstract Full Text Full Text PDF PubMed Scopus (266) Google Scholar, 9Schreiber A. Xiao H. Falk R.J. Jennette J.C. J. Am. Soc. Nephrol. 2006; 17: 3355-3364Crossref PubMed Scopus (87) Google Scholar). In contrast to MPO, membrane-PR3 (mPR3) has a bimodal expression pattern resulting in distinct mPR3low and mPR3high subsets. The percentage of mPR3high neutrophils ranges from 0 to 100%, is genetically determined, and in a large part explained by the HLA region (10Halbwachs-Mecarelli L. Bessou G. Lesavre P. Lopez S. Witko-Sarsat V. FEBS Lett. 1995; 374: 29-33Crossref PubMed Scopus (140) Google Scholar, 11Schreiber A. Busjahn A. Luft F.C. Kettritz R. J. Am. Soc. Nephrol. 2003; 14: 68-75Crossref PubMed Scopus (136) Google Scholar, 12von Vietinghoff S. Busjahn A. Schönemann C. Massenkeil G. Otto B. Luft F.C. Kettritz R. J. Am. Soc. Nephrol. 2006; 17: 3185-3191Crossref PubMed Scopus (20) Google Scholar). Patients with ANCA vasculitis have a higher percentage of mPR3high neutrophils that correlates with disease parameters (13Witko-Sarsat V. Lesavre P. Lopez S. Bessou G. Hieblot C. Prum B. Noël L.H. Guillevin L. Ravaud P. Sermet-Gaudelus I. Timsit J. Grünfeld J.P. Halbwachs-Mecarelli L. J. Am. Soc. Nephrol. 1999; 10: 1224-1233PubMed Google Scholar, 14Rarok A.A. Stegeman C.A. Limburg P.C. Kallenberg C.G. J. Am. Soc. Nephrol. 2002; 13: 2232-2238Crossref PubMed Scopus (141) Google Scholar, 15Schreiber A. Otto B. Ju X. Zenke M. Goebel U. Luft F.C. Kettritz R. J. Am. Soc. Nephrol. 2005; 16: 2216-2224Crossref PubMed Scopus (31) Google Scholar). In vitro experiments indicate that mPR3high neutrophils respond with increased PR3-ANCA-mediated superoxide generation and degranulation, whereas other stimuli triggered a similar response in both neutrophil subsets (16Schreiber A. Luft F.C. Kettritz R. Kidney Int. 2004; 65: 2172-2183Abstract Full Text Full Text PDF PubMed Scopus (91) Google Scholar). Neutrophil antigen B1 (NB1, CD177) is exclusively expressed in and on mPR3high neutrophils and functions as a presenting receptor for PR3 on the cell membrane on this neutrophil subset (17Bauer S. Abdgawad M. Gunnarsson L. Segelmark M. Tapper H. Hellmark T. J. Leukoc. Biol. 2007; 81: 458-464Crossref PubMed Scopus (93) Google Scholar, 18von Vietinghoff S. Tunnemann G. Eulenberg C. Wellner M. Cristina Cardoso M. Luft F.C. Kettritz R. Blood. 2007; 109: 4487-4493Crossref PubMed Scopus (100) Google Scholar, 19Korkmaz B. Kuhl A. Bayat B. Santoso S. Jenne D.E. J. Biol. Chem. 2008; 283: 35976-35982Abstract Full Text Full Text PDF PubMed Scopus (49) Google Scholar). In a recent report, the percentage of NB1-expressing neutrophils was higher in ANCA vasculitis patients, compared with healthy controls. Furthermore, within the ANCA group, the percentage was higher in those patients who had relapsing disease (20Hu N. Westra J. Huitema M.G. Bijl M. Brouwer E. Stegeman C.A. Heeringa P. Limburg P.C. Kallenberg C.G. Arthritis Rheum. 2009; 60: 1548-1557Crossref PubMed Scopus (61) Google Scholar). Together, these data indicate that the mNB1pos/PR3high phenotype is clinically relevant in ANCA vasculitis.NB1 is a GPI-anchored molecule that lacks an intracellular domain. The link between mPR3 presentation by the non-signaling NB1 receptor and neutrophil activation in response to PR3-ANCA is still missing. We hypothesized that additional components that have not yet been identified must be recruited into a larger NB1 signaling complex. Examples from other GPI-linked receptors implicate candidates such as various integrins (21Bohuslav J. Horejsi V. Hansmann C. Stöckl J. Weidle U.H. Majdic O. Bartke I. Knapp W. Stockinger H. J. Exp. Med. 1995; 181: 1381-1390Crossref PubMed Scopus (355) Google Scholar, 22Watanabe T. Sendo F. Biochem. Biophys. Res. Commun. 2002; 294: 692-694Crossref PubMed Scopus (16) Google Scholar, 23Blasi F. Carmeliet P. Nat. Rev. Mol. Cell Biol. 2002; 3: 932-943Crossref PubMed Scopus (1063) Google Scholar, 25Petty H.R. Todd 3rd, R.F. Immunol. Today. 1996; 17: 209-212Abstract Full Text PDF PubMed Scopus (145) Google Scholar, 26Stöckl J. Majdic O. Pickl W.F. Rosenkranz A. Prager E. Gschwantler E. Knapp W. J. Immunol. 1995; 154: 5452-5463PubMed Google Scholar), gp130 (23Blasi F. Carmeliet P. Nat. Rev. Mol. Cell Biol. 2002; 3: 932-943Crossref PubMed Scopus (1063) Google Scholar), the transmembrane protein tyrosine kinase Ret (24Klein R.D. Sherman D. Ho W.H. Stone D. Bennett G.L. Moffat B. Vandlen R. Simmons L. Gu Q. Hongo J.A. Devaux B. Poulsen K. Armanini M. Nozaki C. Asai N. Goddard A. Phillips H. Henderson C.E. Takahashi M. Rosenthal A. Nature. 1997; 387: 717-721Crossref PubMed Scopus (345) Google Scholar), and the formyl peptide receptor-like 1 (FPRL1) (23Blasi F. Carmeliet P. Nat. Rev. Mol. Cell Biol. 2002; 3: 932-943Crossref PubMed Scopus (1063) Google Scholar) that are often dynamically organized in lipid rafts. We aimed to identify constituents of the PR3-NB1 receptor complex that are functionally important when PR3-ANCA activate neutrophils. Clarification of these initial signaling processes may identify novel treatment targets for ANCA vasculitis.DISCUSSIONOur data enhance our earlier findings, that PR3 is presented on the membrane of a neutrophil subset by the GPI-anchored NB1 receptor (18von Vietinghoff S. Tunnemann G. Eulenberg C. Wellner M. Cristina Cardoso M. Luft F.C. Kettritz R. Blood. 2007; 109: 4487-4493Crossref PubMed Scopus (100) Google Scholar). NB1 lacks a transmembrane domain that is necessary for intracellular signal transduction and subsequent neutrophil activation by PR3-ANCA. We show here that PR3-ANCA stimulates degranulation and superoxide production in the mNB1/mPR3-expressing subset only and that the β2-integrin Mac-1 is part of a larger PR3-NB1 signaling complex. The CD11b and CD18 chain are functionally important for neutrophil activation via the NB1 signaling complex and are at work when degranulation and superoxide generation in mNB1pos/mPR3high neutrophils are stimulated by PR3-ANCA. The data also suggest that NB1 and Mac-1 cooperate by receptor-receptor interaction rather than ligand-dependent co-stimulation.PR3-ANCA and MPO-ANCA activate cytokine-primed neutrophils. PR3, but not MPO shows a bimodal membrane expression pattern on neutrophils. High mPR3 expression is only found on those neutrophils that co-express the GPI-linked NB1 receptor (17Bauer S. Abdgawad M. Gunnarsson L. Segelmark M. Tapper H. Hellmark T. J. Leukoc. Biol. 2007; 81: 458-464Crossref PubMed Scopus (93) Google Scholar, 18von Vietinghoff S. Tunnemann G. Eulenberg C. Wellner M. Cristina Cardoso M. Luft F.C. Kettritz R. Blood. 2007; 109: 4487-4493Crossref PubMed Scopus (100) Google Scholar, 20Hu N. Westra J. Huitema M.G. Bijl M. Brouwer E. Stegeman C.A. Heeringa P. Limburg P.C. Kallenberg C.G. Arthritis Rheum. 2009; 60: 1548-1557Crossref PubMed Scopus (61) Google Scholar). We performed previously ectopic expression studies showing that NB1 was a sufficient receptor for PR3 (18von Vietinghoff S. Tunnemann G. Eulenberg C. Wellner M. Cristina Cardoso M. Luft F.C. Kettritz R. Blood. 2007; 109: 4487-4493Crossref PubMed Scopus (100) Google Scholar, 35von Vietinghoff S. Eulenberg C. Wellner M. Luft F.C. Kettritz R. Clin Exp Immunol. 2008; 152: 508-516Crossref PubMed Scopus (27) Google Scholar). Korkmaz et al. (19Korkmaz B. Kuhl A. Bayat B. Santoso S. Jenne D.E. J. Biol. Chem. 2008; 283: 35976-35982Abstract Full Text Full Text PDF PubMed Scopus (49) Google Scholar) elegantly showed that a hydrophobic patch of the PR3 molecule mediates membrane binding via NB1 receptors. No data so far explain how PR3-ANCA-mediated neutrophil activation via the GPI-linked non-signaling NB1 receptor can occur. This issue may be even of broader interest, since NB1 is also implicated in other antibody-mediated diseases, such as neonatal neutropenia and transfusion-related acute lung injury (TRALI) and functions as a counter-receptor for PECAM-1 (CD31) (27Sachs U.J. Andrei-Selmer C.L. Maniar A. Weiss T. Paddock C. Orlova V.V. Choi E.Y. Newman P.J. Preissner K.T. Chavakis T. Santoso S. J. Biol. Chem. 2007; 282: 23603-23612Abstract Full Text Full Text PDF PubMed Scopus (158) Google Scholar, 36Pocock C.F. Lucas G.F. Giles C. Vassiliou G. Cwynarski K. Rezvani K. Apperley J.F. Goldman J.M. Br. J. Haematol. 2001; 113: 483-485Crossref PubMed Scopus (19) Google Scholar, 37Sachs U.J. Hattar K. Weissmann N. Bohle R.M. Weiss T. Sibelius U. Bux J. Blood. 2006; 107: 1217-1219Crossref PubMed Scopus (133) Google Scholar, 38Bayat B. Werth S. Sachs U.J. Newman D.K. Newman P.J. Santoso S. J. Immunol. 2010; 184: 3889-3896Crossref PubMed Scopus (53) Google Scholar). We performed parallel assessment of extracellular superoxide and intracellular oxidants in ANCA-stimulated neutrophils. Our data clearly confirm that the mNB1/mPR3 phenotype matters for degranulation and for the NADPH oxidase-mediated extracellular superoxide generation to PR3-ANCA. Interestingly, these head-to-head comparisons with respect to the respiratory burst indicate that both the mNB1/mPR3low and mNB1/mPR3high phenotype responded to PR3-ANCA with similar intracellular oxidant production. Thus, there is only an apparent controversy between our data and a recent study by Hu et al. (20Hu N. Westra J. Huitema M.G. Bijl M. Brouwer E. Stegeman C.A. Heeringa P. Limburg P.C. Kallenberg C.G. Arthritis Rheum. 2009; 60: 1548-1557Crossref PubMed Scopus (61) Google Scholar). These investigators separated neutrophils in mNB1/mPR3low and mNB1/mPR3high subset followed by anti-PR3 mAb stimulation. Respiratory burst was measured by DHR oxidation. Results were variable, but suggested that similar amounts of intracellular oxidants were generated by both cell subsets. We believe that our parallel experiments settle a potentially time- and labor-consuming conflict. It is conceivable that the mNB1/mPR3 phenotype causes differences in ANCA internalization that in turn result in differences between extra- and intracellular oxidant production. Future studies are needed to address this issue.GPI-linked receptors utilize transmembrane proteins to initiate cell signaling and activation. We detected several signaling molecules that were complexed with NB1 in carefully digitonin-extracted membranes. We focused on the transmembrane integrin chains CD11b and CD18 that form the β2-integrin Mac-1 because they were previously shown to cooperate with GPI-anchored receptors in neutrophils. For example Mac-1 cooperates with the GPI-linked receptors for uPA, CD14, FcgIII and GPI-80 in adhesion, phagocytosis, chemotactic movement, and respiratory burst (21Bohuslav J. Horejsi V. Hansmann C. Stöckl J. Weidle U.H. Majdic O. Bartke I. Knapp W. Stockinger H. J. Exp. Med. 1995; 181: 1381-1390Crossref PubMed Scopus (355) Google Scholar, 22Watanabe T. Sendo F. Biochem. Biophys. Res. Commun. 2002; 294: 692-694Crossref PubMed Scopus (16) Google Scholar, 25Petty H.R. Todd 3rd, R.F. Immunol. Today. 1996; 17: 209-212Abstract Full Text PDF PubMed Scopus (145) Google Scholar, 26Stöckl J. Majdic O. Pickl W.F. Rosenkranz A. Prager E. Gschwantler E. Knapp W. J. Immunol. 1995; 154: 5452-5463PubMed Google Scholar, 39Peyron P. Bordier C. N′Diaye E.N. Maridonneau-Parini I. J. Immunol. 2000; 165: 5186-5191Crossref PubMed Scopus (185) Google Scholar). Previously, David et al. (40David A. Kacher Y. Specks U. Aviram I. J. Leukoc. Biol. 2003; 74: 551-557Crossref PubMed Scopus (48) Google Scholar) described co-localization of mPR3 and CD11b/CD18 in neutrophil plasma membrane preparations. Our data extend this report by showing that the mPR3-presenting NB1 receptor and Mac-1 co-immunoprecipitate, interact physically and co-localize on the neutrophil membrane and that all 3 molecules, namely PR3, NB1, and Mac-1 exist in lipid rafts. Lipid rafts provide a highly interactive platform allowing the dynamic regulation of signaling proteins.Three α-subunits (CD11a, CD11b, CD11c) are expressed together with the CD18 subunit on the neutrophil cell surface. Analysis of direct protein-protein interaction showed that NB1 could also react with CD11a. However, this reaction was not observed on the cell level; CD11a/CD18-transfected cells did not interact with immobilized NB1 protein. Together with the fact that CD11b, compared with CD11a, exist in higher surface density, our results implicate that CD11b/CD18 acts as the major co-receptor for NB1 in neutrophils. However, based on our MS/MS results, it is very likely that more NB1-associated molecules might exist in an even larger membrane-associated signaling complex. The functional role of these molecules needs to be explored in future studies.Using different Mac-1 blocking antibodies to either CD11b or CD18, and even different epitopes to the latter, we demonstrate that both β2-integrin transmembrane chains are functional important for PR3-ANCA-induced degranulation and superoxide generation. We reasoned that Mac-1 could participate in at least two ways in PR3-ANCA-initiated activation. One could envision receptor-receptor interaction between Mac-1 and NB1 and alternatively, a ligand-dependent co-stimulatory outside-in Mac-1 signal. Our data using strict non-adherent conditions strongly suggest that NB1-Mac-1 receptor interactions occur and that no β2-integrin outside-in signaling is needed. Furthermore, we show by different approaches that the extracellular NB1 and Mac-1 domains interact with each other and that both molecules co-localize on the neutrophil plasma membrane. Several models of inter-receptor interactions are conceivable, including receptor coordination, compartmentalization, lateral transactivation, and modulation of receptor expression (25Petty H.R. Todd 3rd, R.F. Immunol. Today. 1996; 17: 209-212Abstract Full Text PDF PubMed Scopus (145) Google Scholar, 41Miranti C.K. Brugge J.S. Nat Cell Biol. 2002; 4: E83-E90Crossref PubMed Scopus (685) Google Scholar). Future experiments will identify the specific mechanisms that are at work.Our results could become highly clinically relevant. We identified Mac-1 as a new member of a larger NB1 membrane complex. We provide evidence that Mac-1 is functionally important for NB1-mediated neutrophil activation by PR3-ANCA. We suggest that targeting the PR3-NB1-Mac-1 signaling complex might be a novel strategy to block PR3-ANCA-mediated neutrophil activation. IntroductionAnti-neutrophil cytoplasmic auto-antibodies (ANCA) 2The abbreviations used are: ANCA, anti-neutrophil cytoplasmic auto-antibodies; GPI, glycosylphosphatidylinositol; fMLP, f-met-leu-phe; PMA, phorbol-2-myristate-13-acetate; DHR, 2.2′-azino-bis (3-ethylbenzthiazoline-6-sulfonicacid), dihydrorhodsamine; DFP, diisopropylfluorophosphate. are found in patients with Wegener granulomatosis, microscopic polyangitis, Churg-Strauss syndrome, and necrotizing crescentic glomerulonephritis (1van 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. Hauu The T. Lancet. 1985; i: 425-429Abstract Scopus (1395) Google Scholar, 2Falk R.J. Jennette J.C. N. Engl. J. Med. 1988; 318: 1651-1657Crossref PubMed Scopus (1227) Google Scholar). PR3- and MPO-ANCA binding to their target antigens on the membrane of neutrophils and monocytes leads to cell activation (3Falk R.J. Terrell R.S. Charles L.A. Jennette J.C. Proc. Natl. Acad. Sci. U.S.A. 1990; 87: 4115-4119Crossref PubMed Scopus (1100) Google Scholar, 4Savage C.O. Pottinger B.E. Gaskin G. Pusey C.D. Pearson J.D. Am. J. Pathol. 1992; 141: 335-342PubMed Google Scholar). ANCA pathogenicity and the pivotal role of the ANCA-neutrophil interaction were established in several animal models (5Xiao H. Heeringa P. Hu P. Liu Z. Zhao M. Aratani Y. Maeda N. Falk R.J. Jennette J.C. J. Clin. Invest. 2002; 110: 955-963Crossref PubMed Scopus (986) Google Scholar, 6Pfister H. Ollert M. Froehlich L.F. Quantanilla-Martinez L. Colby T.V. Specks U. Jenne D. Blood. 2004; 104: 1411-1418Crossref PubMed Scopus (218) Google Scholar, 7Little M.A. Smyth C.L. Yadav R. Ambrose L. Cook H.T. Nourshargh S. Pusey C.D. Blood. 2005; 106: 2050-2058Crossref PubMed Scopus (238) Google Scholar, 8Xiao H. Heeringa P. Liu Z. Huugen D. Hu P. Maeda N. Falk R.J. Jennette J.C. Am. J. Pathol. 2005; 167: 39-45Abstract Full Text Full Text PDF PubMed Scopus (266) Google Scholar, 9Schreiber A. Xiao H. Falk R.J. Jennette J.C. J. Am. Soc. Nephrol. 2006; 17: 3355-3364Crossref PubMed Scopus (87) Google Scholar). In contrast to MPO, membrane-PR3 (mPR3) has a bimodal expression pattern resulting in distinct mPR3low and mPR3high subsets. The percentage of mPR3high neutrophils ranges from 0 to 100%, is genetically determined, and in a large part explained by the HLA region (10Halbwachs-Mecarelli L. Bessou G. Lesavre P. Lopez S. Witko-Sarsat V. FEBS Lett. 1995; 374: 29-33Crossref PubMed Scopus (140) Google Scholar, 11Schreiber A. Busjahn A. Luft F.C. Kettritz R. J. Am. Soc. Nephrol. 2003; 14: 68-75Crossref PubMed Scopus (136) Google Scholar, 12von Vietinghoff S. Busjahn A. Schönemann C. Massenkeil G. Otto B. Luft F.C. Kettritz R. J. Am. Soc. Nephrol. 2006; 17: 3185-3191Crossref PubMed Scopus (20) Google Scholar). Patients with ANCA vasculitis have a higher percentage of mPR3high neutrophils that correlates with disease parameters (13Witko-Sarsat V. Lesavre P. Lopez S. Bessou G. Hieblot C. Prum B. Noël L.H. Guillevin L. Ravaud P. Sermet-Gaudelus I. Timsit J. Grünfeld J.P. Halbwachs-Mecarelli L. J. Am. Soc. Nephrol. 1999; 10: 1224-1233PubMed Google Scholar, 14Rarok A.A. Stegeman C.A. Limburg P.C. Kallenberg C.G. J. Am. Soc. Nephrol. 2002; 13: 2232-2238Crossref PubMed Scopus (141) Google Scholar, 15Schreiber A. Otto B. Ju X. Zenke M. Goebel U. Luft F.C. Kettritz R. J. Am. Soc. Nephrol. 2005; 16: 2216-2224Crossref PubMed Scopus (31) Google Scholar). In vitro experiments indicate that mPR3high neutrophils respond with increased PR3-ANCA-mediated superoxide generation and degranulation, whereas other stimuli triggered a similar response in both neutrophil subsets (16Schreiber A. Luft F.C. Kettritz R. Kidney Int. 2004; 65: 2172-2183Abstract Full Text Full Text PDF PubMed Scopus (91) Google Scholar). Neutrophil antigen B1 (NB1, CD177) is exclusively expressed in and on mPR3high neutrophils and functions as a presenting receptor for PR3 on the cell membrane on this neutrophil subset (17Bauer S. Abdgawad M. Gunnarsson L. Segelmark M. Tapper H. Hellmark T. J. Leukoc. Biol. 2007; 81: 458-464Crossref PubMed Scopus (93) Google Scholar, 18von Vietinghoff S. Tunnemann G. Eulenberg C. Wellner M. Cristina Cardoso M. Luft F.C. Kettritz R. Blood. 2007; 109: 4487-4493Crossref PubMed Scopus (100) Google Scholar, 19Korkmaz B. Kuhl A. Bayat B. Santoso S. Jenne D.E. J. Biol. Chem. 2008; 283: 35976-35982Abstract Full Text Full Text PDF PubMed Scopus (49) Google Scholar). In a recent report, the percentage of NB1-expressing neutrophils was higher in ANCA vasculitis patients, compared with healthy controls. Furthermore, within the ANCA group, the percentage was higher in those patients who had relapsing disease (20Hu N. Westra J. Huitema M.G. Bijl M. Brouwer E. Stegeman C.A. Heeringa P. Limburg P.C. Kallenberg C.G. Arthritis Rheum. 2009; 60: 1548-1557Crossref PubMed Scopus (61) Google Scholar). Together, these data indicate that the mNB1pos/PR3high phenotype is clinically relevant in ANCA vasculitis.NB1 is a GPI-anchored molecule that lacks an intracellular domain. The link between mPR3 presentation by the non-signaling NB1 receptor and neutrophil activation in response to PR3-ANCA is still missing. We hypothesized that additional components that have not yet been identified must be recruited into a larger NB1 signaling complex. Examples from other GPI-linked receptors implicate candidates such as various integrins (21Bohuslav J. Horejsi V. Hansmann C. Stöckl J. Weidle U.H. Majdic O. Bartke I. Knapp W. Stockinger H. J. Exp. Med. 1995; 181: 1381-1390Crossref PubMed Scopus (355) Google Scholar, 22Watanabe T. Sendo F. Biochem. Biophys. Res. Commun. 2002; 294: 692-694Crossref PubMed Scopus (16) Google Scholar, 23Blasi F. Carmeliet P. Nat. Rev. Mol. Cell Biol. 2002; 3: 932-943Crossref PubMed Scopus (1063) Google Scholar, 25Petty H.R. Todd 3rd, R.F. Immunol. Today. 1996; 17: 209-212Abstract Full Text PDF PubMed Scopus (145) Google Scholar, 26Stöckl J. Majdic O. Pickl W.F. Rosenkranz A. Prager E. Gschwantler E. Knapp W. J. Immunol. 1995; 154: 5452-5463PubMed Google Scholar), gp130 (23Blasi F. Carmeliet P. Nat. Rev. Mol. Cell Biol. 2002; 3: 932-943Crossref PubMed Scopus (1063) Google Scholar), the transmembrane protein tyrosine kinase Ret (24Klein R.D. Sherman D. Ho W.H. Stone D. Bennett G.L. Moffat B. Vandlen R. Simmons L. Gu Q. Hongo J.A. Devaux B. Poulsen K. Armanini M. Nozaki C. Asai N. Goddard A. Phillips H. Henderson C.E. Takahashi M. Rosenthal A. Nature. 1997; 387: 717-721Crossref PubMed Scopus (345) Google Scholar), and the formyl peptide receptor-like 1 (FPRL1) (23Blasi F. Carmeliet P. Nat. Rev. Mol. Cell Biol. 2002; 3: 932-943Crossref PubMed Scopus (1063) Google Scholar) that are often dynamically organized in lipid rafts. We aimed to identify constituents of the PR3-NB1 receptor complex that are functionally important when PR3-ANCA activate neutrophils. Clarification of these initial signaling processes may identify novel treatment targets for ANCA vasculitis." @default.
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