{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,5]],"date-time":"2026-10-05T17:24:46Z","timestamp":1791221086879,"version":"4.1.0"},"reference-count":44,"publisher":"Oxford University Press (OUP)","issue":"1","license":[{"start":{"date-parts":[[2010,7,1]],"date-time":"2010-07-01T00:00:00Z","timestamp":1277942400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/academic.oup.com\/pages\/standard-publication-reuse-rights"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2010,7,1]]},"abstract":"<jats:title>Abstract<\/jats:title>\n               <jats:p>Anti-neutrophil cytoplasmic Abs (cANCAs) against conformational epitopes of proteinase 3 (PR3) are regarded as an important pathogenic marker in Wegener\u2019s 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 \u03b2-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\u2013\u03b11-protease inhibitor (\u03b11\u2013PI) complexes was even more reduced and often absent, indicating that major antigenic determinants overlap with the active site surface on PR3 that associates with \u03b11-PI. Similarly, the mouse mAbs CLB12.8 and 6A6 also did not react with gibbon PR3 and PR3\u2013\u03b11-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 \u03b11-PI to PR3.<\/jats:p>","DOI":"10.4049\/jimmunol.0903887","type":"journal-article","created":{"date-parts":[[2010,6,8]],"date-time":"2010-06-08T00:20:28Z","timestamp":1275956428000},"page":"387-399","source":"Crossref","is-referenced-by-count":29,"title":["Mapping of Conformational Epitopes on Human Proteinase 3, the Autoantigen of Wegener\u2019s Granulomatosis"],"prefix":"10.1093","volume":"185","author":[{"given":"Angelika","family":"Kuhl","sequence":"first","affiliation":[{"name":"Department of Neuroimmunology, Max-Planck-Institute of Neurobiology , Planegg\/Martinsried ,","place":["Germany"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Brice","family":"Korkmaz","sequence":"additional","affiliation":[{"name":"Department of Neuroimmunology, Max-Planck-Institute of Neurobiology , Planegg\/Martinsried ,","place":["Germany"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bert","family":"Utecht","sequence":"additional","affiliation":[{"name":"Utecht and L\u00fcdemann , Klausdorf\/Schwentine ,","place":["Germany"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Andrea","family":"Kniepert","sequence":"additional","affiliation":[{"name":"Department of Neuroimmunology, Max-Planck-Institute of Neurobiology , Planegg\/Martinsried ,","place":["Germany"]},{"name":"Department of Biology, University of Konstanz , Konstanz ,","place":["Germany"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ulf","family":"Sch\u00f6nermarck","sequence":"additional","affiliation":[{"name":"University Hospital Munich-Gro\u00dfhadern , Munich ,","place":["Germany"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ulrich","family":"Specks","sequence":"additional","affiliation":[{"name":"Thoracic Diseases Research Unit, Division of Pulmonary and Critical Care Medicine, Mayo Clinic and Foundation , Rochester, MN 55905"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Dieter E","family":"Jenne","sequence":"additional","affiliation":[{"name":"Department of Neuroimmunology, Max-Planck-Institute of Neurobiology , Planegg\/Martinsried ,","place":["Germany"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"286","published-online":{"date-parts":[[2010,7,1]]},"reference":[{"key":"2025032411344371100_r1","doi-asserted-by":"crossref","first-page":"661","DOI":"10.1038\/ncprheum0355","article-title":"Mechanisms of Disease: pathogenesis and treatment of ANCA-associated vasculitides","volume":"2","author":"Kallenberg","year":"2006","journal-title":"Nat. Clin. Pract. Rheumatol."},{"key":"2025032411344371100_r2","doi-asserted-by":"crossref","first-page":"84","DOI":"10.1196\/annals.1398.010","article-title":"Human proteinase 3 (PR3) and its binding molecules: implications for inflammatory and PR3-related autoimmune responses","volume":"1109","author":"M\u00fcller","year":"2007","journal-title":"Ann. N.Y. Acad. Sci."},{"key":"2025032411344371100_r3","doi-asserted-by":"crossref","first-page":"3","DOI":"10.1189\/jlb.1202611","article-title":"Neutrophil-activating potential of antineutrophil cytoplasm autoantibodies","volume":"74","author":"Rarok","year":"2003","journal-title":"J. Leukoc. Biol."},{"key":"2025032411344371100_r4","doi-asserted-by":"crossref","first-page":"263","DOI":"10.1186\/ar99","article-title":"What you should know about PR3-ANCA. Conformational requirements of proteinase 3 (PR3) for enzymatic activity and recognition by PR3-ANCA","volume":"2","author":"Specks","year":"2000","journal-title":"Arthritis Res."},{"key":"2025032411344371100_r5","doi-asserted-by":"crossref","first-page":"458","DOI":"10.1189\/jlb.0806514","article-title":"Proteinase 3 and CD177 are expressed on the plasma membrane of the same subset of neutrophils","volume":"81","author":"Bauer","year":"2007","journal-title":"J. Leukoc. Biol."},{"key":"2025032411344371100_r6","doi-asserted-by":"crossref","first-page":"4487","DOI":"10.1182\/blood-2006-10-055327","article-title":"NB1 mediates surface expression of the ANCA antigen proteinase 3 on human neutrophils","volume":"109","author":"von Vietinghoff","year":"2007","journal-title":"Blood"},{"key":"2025032411344371100_r7","doi-asserted-by":"crossref","first-page":"1548","DOI":"10.1002\/art.24442","article-title":"Coexpression of CD177 and membrane proteinase 3 on neutrophils in antineutrophil cytoplasmic autoantibody-associated systemic vasculitis: anti-proteinase 3-mediated neutrophil activation is independent of the role of CD177-expressing neutrophils","volume":"60","author":"Hu","year":"2009","journal-title":"Arthritis Rheum."},{"key":"2025032411344371100_r8","doi-asserted-by":"crossref","first-page":"1009","DOI":"10.1111\/j.1523-1755.2004.00849.x","article-title":"Autoantibodies to neutrophil cytoplasmic antigens (ANCA) do not bind to polymorphonuclear neutrophils in blood","volume":"66","author":"Abdel-Salam","year":"2004","journal-title":"Kidney Int."},{"key":"2025032411344371100_r9","doi-asserted-by":"crossref","first-page":"611","DOI":"10.7326\/0003-4819-147-9-200711060-00005","article-title":"Antiproteinase 3 antineutrophil cytoplasmic antibodies and disease activity in Wegener granulomatosis","volume":"147","author":"Finkielman","year":"2007","journal-title":"Ann. Intern. Med."},{"key":"2025032411344371100_r10","doi-asserted-by":"crossref","first-page":"170","DOI":"10.1046\/j.1365-2249.2001.01420.x","article-title":"Anti-neutrophil cytoplasmic antibodies (ANCA) from patients with systemic vasculitis recognize restricted epitopes of proteinase 3 involving the catalytic site","volume":"123","author":"Griffith","year":"2001","journal-title":"Clin. Exp. Immunol."},{"key":"2025032411344371100_r11","doi-asserted-by":"crossref","first-page":"147","DOI":"10.1046\/j.1523-1755.2001.00475.x","article-title":"Antineutrophil cytoplasmic antibodies to proteinase 3 in Wegener\u2019s granulomatosis: epitope analysis using synthetic peptides","volume":"59","author":"Van Der Geld","year":"2001","journal-title":"Kidney Int."},{"key":"2025032411344371100_r12","doi-asserted-by":"crossref","first-page":"4722","DOI":"10.4049\/jimmunol.152.9.4722","article-title":"Epitopes on proteinase-3 recognized by antibodies from patients with Wegener\u2019s granulomatosis","volume":"152","author":"Williams","year":"1994","journal-title":"J. Immunol."},{"key":"2025032411344371100_r13","doi-asserted-by":"crossref","first-page":"164","DOI":"10.1111\/j.1365-2249.2004.02314.x","article-title":"Epitope mapping of anti-PR3 antibodies using chimeric human\/mouse PR3 recombinant proteins","volume":"135","author":"Selga","year":"2004","journal-title":"Clin. Exp. Immunol."},{"key":"2025032411344371100_r14","doi-asserted-by":"crossref","first-page":"112","DOI":"10.1111\/j.1365-2249.1995.tb06644.x","article-title":"Epitope mapping of anti-proteinase 3 and anti-myeloperoxidase antibodies","volume":"102","author":"Chang","year":"1995","journal-title":"Clin. Exp. Immunol."},{"key":"2025032411344371100_r15","first-page":"249","article-title":"Characterization of monoclonal antibodies to proteinase-3 and application in the study of epitopes for classical anti-neutrophil cytoplasm antibodies","volume":"3","author":"Sommarin","year":"1995","journal-title":"Exp. Nephrol."},{"key":"2025032411344371100_r16","doi-asserted-by":"crossref","first-page":"487","DOI":"10.1046\/j.1365-2249.1999.01079.x","article-title":"Characterization of monoclonal antibodies to proteinase 3 (PR3) as candidate tools for epitope mapping of human anti-PR3 autoantibodies","volume":"118","author":"Van Der Geld","year":"1999","journal-title":"Clin. Exp. Immunol."},{"key":"2025032411344371100_r17","doi-asserted-by":"crossref","first-page":"187","DOI":"10.1016\/S0014-5793(97)00418-3","article-title":"Cloning and functional expression of the murine homologue of proteinase 3: implications for the design of murine models of vasculitis","volume":"408","author":"Jenne","year":"1997","journal-title":"FEBS Lett."},{"key":"2025032411344371100_r18","doi-asserted-by":"crossref","first-page":"9813","DOI":"10.1073\/pnas.95.17.9813","article-title":"New enzyme lineages by subdomain shuffling","volume":"95","author":"H\u00f6pfner","year":"1998","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"2025032411344371100_r19","doi-asserted-by":"crossref","first-page":"111","DOI":"10.1016\/S0022-1759(97)00203-2","article-title":"Capture-ELISA based on recombinant PR3 is sensitive for PR3-ANCA testing and allows detection of PR3 and PR3-ANCA\/PR3 immunecomplexes","volume":"211","author":"Sun","year":"1998","journal-title":"J. Immunol. Methods"},{"key":"2025032411344371100_r20","doi-asserted-by":"crossref","first-page":"959","DOI":"10.1016\/0092-8674(89)90752-6","article-title":"Down-regulation of a serine protease, myeloblastin, causes growth arrest and differentiation of promyelocytic leukemia cells","volume":"59","author":"Bories","year":"1989","journal-title":"Cell"},{"key":"2025032411344371100_r21","doi-asserted-by":"crossref","first-page":"1709","DOI":"10.1084\/jem.172.6.1709","article-title":"Cloning of cDNA for proteinase 3: a serine protease, antibiotic, and autoantigen from human neutrophils","volume":"172","author":"Campanelli","year":"1990","journal-title":"J. Exp. Med."},{"key":"2025032411344371100_r22","doi-asserted-by":"crossref","first-page":"33","DOI":"10.1159\/000133555","article-title":"Localization of the gene encoding proteinase-3 (the Wegener\u2019s granulomatosis autoantigen) to human chromosome band 19p13.3","volume":"64","author":"Sturrock","year":"1993","journal-title":"Cytogenet. Cell Genet."},{"key":"2025032411344371100_r23","doi-asserted-by":"crossref","first-page":"267","DOI":"10.1006\/jmbi.1996.0458","article-title":"The crystal structure of PR3, a neutrophil serine proteinase antigen of Wegener\u2019s granulomatosis antibodies","volume":"261","author":"Fujinaga","year":"1996","journal-title":"J. Mol. Biol."},{"key":"2025032411344371100_r24","doi-asserted-by":"crossref","first-page":"801","DOI":"10.1165\/rcmb.2003-0139OC","article-title":"Design and use of highly specific substrates of neutrophil elastase and proteinase 3","volume":"30","author":"Korkmaz","year":"2004","journal-title":"Am. J. Respir. Cell Mol. Biol."},{"key":"2025032411344371100_r25","doi-asserted-by":"crossref","first-page":"1989","DOI":"10.1074\/jbc.M608700200","article-title":"Influence of charge distribution at the active site surface on the substrate specificity of human neutrophil protease 3 and elastase. A kinetic and molecular modeling analysis","volume":"282","author":"Korkmaz","year":"2007","journal-title":"J. Biol. Chem."},{"key":"2025032411344371100_r26","doi-asserted-by":"crossref","first-page":"227","DOI":"10.1016\/j.biochi.2007.10.009","article-title":"Neutrophil elastase, proteinase 3 and cathepsin G: physicochemical properties, activity and physiopathological functions","volume":"90","author":"Korkmaz","year":"2008","journal-title":"Biochimie"},{"key":"2025032411344371100_r27","doi-asserted-by":"crossref","first-page":"5305","DOI":"10.1016\/j.febslet.2005.08.056","article-title":"Differences between human proteinase 3 and neutrophil elastase and their murine homologues are relevant for murine model experiments","volume":"579","author":"Wiesner","year":"2005","journal-title":"FEBS Lett."},{"key":"2025032411344371100_r28","doi-asserted-by":"crossref","first-page":"39074","DOI":"10.1074\/jbc.M202918200","article-title":"Discriminating between the activities of human neutrophil elastase and proteinase 3 using serpin-derived fluorogenic substrates","volume":"277","author":"Korkmaz","year":"2002","journal-title":"J. Biol. Chem."},{"key":"2025032411344371100_r29","doi-asserted-by":"crossref","first-page":"747","DOI":"10.1165\/ajrcmb.24.6.4147","article-title":"Anti-proteinase 3 antibody activation of neutrophils can be inhibited by \u03b11-antitrypsin","volume":"24","author":"Rooney","year":"2001","journal-title":"Am. J. Respir. Cell Mol. Biol."},{"key":"2025032411344371100_r30","doi-asserted-by":"crossref","first-page":"3452","DOI":"10.1074\/jbc.M510564200","article-title":"Active site distortion is sufficient for proteinase inhibition by serpins: structure of the covalent complex of \u03b11-proteinase inhibitor with porcine pancreatic elastase","volume":"281","author":"Dementiev","year":"2006","journal-title":"J. Biol. Chem."},{"key":"2025032411344371100_r31","doi-asserted-by":"crossref","first-page":"119","DOI":"10.1016\/S0065-3233(02)61004-6","article-title":"Molecular recognition in antibody-antigen complexes","volume":"61","author":"Sundberg","year":"2002","journal-title":"Adv. Protein Chem."},{"key":"2025032411344371100_r32","doi-asserted-by":"crossref","first-page":"482","DOI":"10.1038\/nsb930","article-title":"X-ray snapshots of the maturation of an antibody response to a protein antigen","volume":"10","author":"Li","year":"2003","journal-title":"Nat. Struct. Biol."},{"key":"2025032411344371100_r33","doi-asserted-by":"crossref","first-page":"35976","DOI":"10.1074\/jbc.M806754200","article-title":"A hydrophobic patch on proteinase 3, the target of autoantibodies in Wegener granulomatosis, mediates membrane binding via NB1 receptors","volume":"283","author":"Korkmaz","year":"2008","journal-title":"J. Biol. Chem."},{"key":"2025032411344371100_r34","doi-asserted-by":"crossref","first-page":"284","DOI":"10.1016\/j.biochi.2007.09.007","article-title":"Multifaceted roles of human elafin and secretory leukocyte proteinase inhibitor (SLPI), two serine protease inhibitors of the chelonianin family","volume":"90","author":"Moreau","year":"2008","journal-title":"Biochimie"},{"key":"2025032411344371100_r35","doi-asserted-by":"crossref","first-page":"310","DOI":"10.1006\/jmbi.1993.1387","article-title":"Crystallization of a complex between an elastase-specific inhibitor elafin and porcine pancreatic elastase","volume":"232","author":"Tsunemi","year":"1993","journal-title":"J. Mol. Biol."},{"key":"2025032411344371100_r36","doi-asserted-by":"crossref","first-page":"19896","DOI":"10.1074\/jbc.M901471200","article-title":"Catalytic activity and inhibition of wegener antigen proteinase 3 on the cell surface of human polymorphonuclear neutrophils","volume":"284","author":"Korkmaz","year":"2009","journal-title":"J. Biol. Chem."},{"key":"2025032411344371100_r37","doi-asserted-by":"crossref","first-page":"117","DOI":"10.1016\/0014-5793(92)80955-G","article-title":"Determination of proteinase 3-\u03b1 1-antitrypsin complexes in inflammatory fluids","volume":"314","author":"Dolman","year":"1992","journal-title":"FEBS Lett."},{"key":"2025032411344371100_r38","doi-asserted-by":"crossref","first-page":"405","DOI":"10.1111\/j.1365-2249.1993.tb08192.x","article-title":"Relevance of classic anti-neutrophil cytoplasmic autoantibody (C-ANCA)-mediated inhibition of proteinase 3-\u03b11-antitrypsin complexation to disease activity in Wegener\u2019s granulomatosis","volume":"93","author":"Dolman","year":"1993","journal-title":"Clin. Exp. Immunol."},{"key":"2025032411344371100_r39","doi-asserted-by":"crossref","first-page":"562","DOI":"10.1046\/j.1365-2249.2002.01926.x","article-title":"Interference of PR3-ANCA with the enzymatic activity of PR3: differences in patients during active disease or remission of Wegener\u2019s granulomatosis","volume":"129","author":"van der Geld","year":"2002","journal-title":"Clin. Exp. Immunol."},{"key":"2025032411344371100_r40","doi-asserted-by":"crossref","first-page":"409","DOI":"10.1111\/j.1365-2249.1992.tb05860.x","article-title":"Interference of Wegener\u2019s granulomatosis autoantibodies with neutrophil proteinase 3 activity","volume":"90","author":"van de Wiel","year":"1992","journal-title":"Clin. Exp. Immunol."},{"key":"2025032411344371100_r41","doi-asserted-by":"crossref","first-page":"786","DOI":"10.1046\/j.1365-2362.1996.2070553.x","article-title":"Complexes between proteinase 3, \u03b11-antitrypsin and proteinase 3 anti-neutrophil cytoplasm autoantibodies: a comparison between \u03b11-antitrypsin PiZ allele carriers and non-carriers with Wegener\u2019s granulomatosis","volume":"26","author":"Baslund","year":"1996","journal-title":"Eur. J. Clin. Invest."},{"key":"2025032411344371100_r42","doi-asserted-by":"crossref","first-page":"97","DOI":"10.1007\/978-1-4757-9182-2_15","article-title":"Studies to demonstrate inhibition of functional activity of neutrophil lysosomal enzymes with ANCA","volume":"336","author":"Chang","year":"1993","journal-title":"Adv. Exp. Med. Biol."},{"key":"2025032411344371100_r43","doi-asserted-by":"crossref","first-page":"1528","DOI":"10.1038\/ki.1995.216","article-title":"Inhibition of proteinase 3 by ANCA and its correlation with disease activity in Wegener\u2019s granulomatosis","volume":"47","author":"Daouk","year":"1995","journal-title":"Kidney Int."},{"key":"2025032411344371100_r44","doi-asserted-by":"crossref","first-page":"543","DOI":"10.1111\/j.1365-2796.1994.tb00842.x","article-title":"Strong link between the alpha 1-antitrypsin PiZ allele and Wegener\u2019s granulomatosis","volume":"236","author":"Elzouki","year":"1994","journal-title":"J. Intern. Med."}],"container-title":["The Journal of Immunology"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/academic.oup.com\/jimmunol\/article-pdf\/185\/1\/387\/62470468\/0903887.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"syndication"},{"URL":"https:\/\/academic.oup.com\/jimmunol\/article-pdf\/185\/1\/387\/62470468\/0903887.pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,3,28]],"date-time":"2025-03-28T20:33:02Z","timestamp":1743193982000},"score":1,"resource":{"primary":{"URL":"https:\/\/academic.oup.com\/jimmunol\/article\/185\/1\/387\/7977356"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2010,7,1]]},"references-count":44,"journal-issue":{"issue":"1","published-print":{"date-parts":[[2010,7,1]]}},"URL":"https:\/\/doi.org\/10.4049\/jimmunol.0903887","relation":{},"ISSN":["0022-1767","1550-6606"],"issn-type":[{"value":"0022-1767","type":"print"},{"value":"1550-6606","type":"electronic"}],"subject":[],"published-other":{"date-parts":[[2010,7]]},"published":{"date-parts":[[2010,7,1]]}}}