{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,11,1]],"date-time":"2026-11-01T17:54:05Z","timestamp":1793555645709,"version":"4.5.0"},"reference-count":38,"publisher":"Ovid Technologies (Wolters Kluwer Health)","issue":"5","funder":[{"DOI":"10.13039\/501100001659","name":"Deutsche Forschungsgemeinschaft","doi-asserted-by":"publisher","award":["KE 576\/10-1"],"award-info":[{"award-number":["KE 576\/10-1"]}],"id":[{"id":"10.13039\/501100001659","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001659","name":"Deutsche Forschungsgemeinschaft","doi-asserted-by":"publisher","award":["SCHR 771\/8-1"],"award-info":[{"award-number":["SCHR 771\/8-1"]}],"id":[{"id":"10.13039\/501100001659","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001659","name":"Deutsche Forschungsgemeinschaft","doi-asserted-by":"publisher","award":["394046635\u2013 SFB 1365"],"award-info":[{"award-number":["394046635\u2013 SFB 1365"]}],"id":[{"id":"10.13039\/501100001659","id-type":"DOI","asserted-by":"publisher"}]},{"name":"R\u00e9gion Centre Val de Loire","award":["2019-00134916"],"award-info":[{"award-number":["2019-00134916"]}]}],"content-domain":{"domain":["lww.com","ovid.com"],"crossmark-restriction":true},"short-container-title":["JASN"],"published-print":{"date-parts":[[2022,5]]},"abstract":"<jats:sec>\n                    <jats:title>Background<\/jats:title>\n                    <jats:p>The ANCA autoantigens proteinase 3 (PR3) and myeloperoxidase (MPO) are exclusively expressed by neutrophils and monocytes. ANCA-mediated activation of these cells is the key driver of the vascular injury process in ANCA-associated vasculitis (AAV), and neutrophil serine proteases (NSPs) are disease mediators. Cathepsin C (CatC) from zymogens activates the proteolytic function of NSPs, including PR3. Lack of NSP zymogen activation results in neutrophils with strongly reduced NSP proteins.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>To explore AAV-relevant consequences of blocking NSP zymogen activation by CatC, we used myeloid cells from patients with Papillon-Lef\u00e8vre syndrome, a genetic deficiency of CatC, to assess NSPs and NSP-mediated endothelial cell injury. We also examined pharmacologic CatC inhibition in neutrophil-differentiated human hematopoietic stem cells, primary human umbilical vein cells, and primary glomerular microvascular endothelial cells.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>Patients with Papillon-Lef\u00e8vre syndrome showed strongly reduced NSPs in neutrophils and monocytes. Neutrophils from these patients produced a negative PR3-ANCA test, presented less PR3 on the surface of viable and apoptotic cells, and caused significantly less damage in human umbilical vein cells. These findings were recapitulated in human stem cells, in which a highly specific CatC inhibitor, but not prednisolone, reduced NSPs without affecting neutrophil differentiation, reduced membrane PR3, and diminished neutrophil activation upon PR3-ANCA but not MPO-ANCA stimulation. Compared with healthy controls, neutrophils from patients with Papillon-Lef\u00e8vre syndrome transferred less proteolytically active NSPs to glomerular microvascular endothelial cells, the cell type targeted in ANCA-induced necrotizing crescentic glomerulonephritis. Finally, both genetic CatC deficiency and pharmacologic inhibition, but not prednisolone, reduced neutrophil-induced glomerular microvascular endothelial cell damage.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusions<\/jats:title>\n                    <jats:p>These findings may offer encouragement for clinical studies of adjunctive CatC inhibitor in patients with PR3-AAV.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1681\/asn.2021081112","type":"journal-article","created":{"date-parts":[[2022,3,15]],"date-time":"2022-03-15T13:00:13Z","timestamp":1647349213000},"page":"936-947","update-policy":"https:\/\/doi.org\/10.1097\/lww.0000000000001000","source":"Crossref","is-referenced-by-count":31,"title":["Targeting Cathepsin C in PR3-ANCA Vasculitis"],"prefix":"10.1681","volume":"33","clinical-trial-number":[{"clinical-trial-number":"nct04594369","registry":"10.18810\/clinical-trials-gov"},{"clinical-trial-number":"nct04817332","registry":"10.18810\/clinical-trials-gov"}],"author":[{"given":"Uwe","family":"Jerke","sequence":"first","affiliation":[{"name":"Experimental and Clinical Research Center, Max Delbrueck Center for Molecular Medicine and Charit\u00e9-Universit\u00e4tsmedizin Berlin, Corporate Member of Freie Universit\u00e4t Berlin, Humboldt-Universit\u00e4t zu Berlin, Berlin Institute of Health, Berlin, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2425-2275","authenticated-orcid":false,"given":"Claudia","family":"Eulenberg-Gustavus","sequence":"additional","affiliation":[{"name":"Experimental and Clinical Research Center, Max Delbrueck Center for Molecular Medicine and Charit\u00e9-Universit\u00e4tsmedizin Berlin, Corporate Member of Freie Universit\u00e4t Berlin, Humboldt-Universit\u00e4t zu Berlin, Berlin Institute of Health, Berlin, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Anthony","family":"Rousselle","sequence":"additional","affiliation":[{"name":"Experimental and Clinical Research Center, Max Delbrueck Center for Molecular Medicine and Charit\u00e9-Universit\u00e4tsmedizin Berlin, Corporate Member of Freie Universit\u00e4t Berlin, Humboldt-Universit\u00e4t zu Berlin, Berlin Institute of Health, Berlin, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Paul","family":"Nicklin","sequence":"additional","affiliation":[{"name":"Boehringer Ingelheim Pharma GmbH & Co., KG, Biberach, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Stefan","family":"Kreideweiss","sequence":"additional","affiliation":[{"name":"Boehringer Ingelheim Pharma GmbH & Co., KG, Biberach, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marc 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Germany"},{"name":"Nephrology and Medical Intensive Care Medicine, Charit\u00e9-Universit\u00e4tsmedizin Berlin, Berlin, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Brice","family":"Korkmaz","sequence":"additional","affiliation":[{"name":"INSERM U-1100 Universit\u00e9 de Tours, Tours, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5821-6718","authenticated-orcid":false,"given":"Ralph","family":"Kettritz","sequence":"additional","affiliation":[{"name":"Experimental and Clinical Research Center, Max Delbrueck Center for Molecular Medicine and Charit\u00e9-Universit\u00e4tsmedizin Berlin, Corporate Member of Freie Universit\u00e4t Berlin, Humboldt-Universit\u00e4t zu Berlin, Berlin Institute of Health, Berlin, Germany"},{"name":"Nephrology and Medical Intensive Care Medicine, Charit\u00e9-Universit\u00e4tsmedizin Berlin, Berlin, 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