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J. Mol. Sci.","IJMS"],"abstract":"<jats:p>C3 glomerulopathy (C3G) and immune complex-mediated membranoproliferative glomerulonephritis (IC-MPGN) are severe complement-mediated kidney diseases. In a substantial proportion of these patients, C3 nephritic factors (C3NeFs) are detected; these autoantibodies stabilize the complement alternative pathway (AP) C3 convertase. Previous studies have investigated and distinguished properdin-dependent and properdin-independent C3NeFs. In this study, we investigated a distinct subset of C3NeFs that are exclusively active in the absence of properdin: properdin-inhibited C3NeFs. A two-step hemolytic AP convertase activity assay was employed to examine convertase activity in patient serum in the presence versus absence of properdin using the properdin inhibitor Salp20. In 7\/16 patients and 1\/23 healthy controls, who showed no convertase stabilization in full serum, convertase stabilization was observed upon properdin inhibition, indicating properdin-inhibited C3NeF activity. Consistent findings were obtained when purified patient Igs were added to properdin-depleted serum. Moreover, in an ELISA-based C3bBb binding assay, 6\/7 patients with properdin-inhibited C3NeFs showed increased convertase binding, which decreased upon addition of properdin. Complement levels in patients with properdin-inhibited C3NeFs were not significantly different from those in the C3NeF-negative group, and properdin levels were generally within the refence range. In conclusion, our results support the existence of properdin-inhibited C3NeFs, thereby further expanding the functional heterogeneity of these autoantibodies. Although their functional relevance under physiological conditions remains unclear, these findings may have important implications for complement-targeted therapies, particularly strategies aimed at properdin inhibition, as the presence of these C3NeFs may predispose to unintended effects.<\/jats:p>","DOI":"10.3390\/ijms27156790","type":"journal-article","created":{"date-parts":[[2026,7,29]],"date-time":"2026-07-29T10:13:47Z","timestamp":1785320027000},"page":"6790","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Characterizing Properdin-Inhibited C3 Nephritic Factors in Patients with Complement-Mediated Kidney Diseases"],"prefix":"10.3390","volume":"27","author":[{"ORCID":"https:\/\/orcid.org\/0009-0001-8200-7315","authenticated-orcid":false,"given":"Kes H.","family":"Stevens","sequence":"first","affiliation":[{"name":"Department of Pediatric Nephrology, Amalia Children\u2019s Hospital, Radboud University Medical Center, 6525 Nijmegen, The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rianne J. F.","family":"Maas","sequence":"additional","affiliation":[{"name":"Department of Pediatric Nephrology, Amalia Children\u2019s Hospital, Radboud University Medical Center, 6525 Nijmegen, The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Elena B.","family":"Volokhina","sequence":"additional","affiliation":[{"name":"Department of Pediatric Nephrology, Amalia Children\u2019s Hospital, Radboud University Medical Center, 6525 Nijmegen, The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9039-635X","authenticated-orcid":false,"given":"Erik J. M.","family":"Toonen","sequence":"additional","affiliation":[{"name":"R&D Department, Hycult Biotech, 5405 Uden, The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1990-1189","authenticated-orcid":false,"given":"Nicole C. A. J.","family":"van de Kar","sequence":"additional","affiliation":[{"name":"Department of Pediatric Nephrology, Amalia Children\u2019s Hospital, Radboud University Medical Center, 6525 Nijmegen, The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3917-6727","authenticated-orcid":false,"given":"Lambertus P. W. J.","family":"van den Heuvel","sequence":"additional","affiliation":[{"name":"Department of Pediatric Nephrology, Amalia Children\u2019s Hospital, Radboud University Medical Center, 6525 Nijmegen, The Netherlands"},{"name":"Department of Human Genetics, Radboud University Medical Center, 6525 Nijmegen, The Netherlands"},{"name":"Department of Pediatrics\/Pediatric Nephrology, University Hospitals Leuven, 3000 Leuven, Belgium"},{"name":"Department of Development and Regeneration, Catholic University Leuven, 3000 Leuven, Belgium"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0750-4493","authenticated-orcid":false,"given":"Marloes A. H. M.","family":"Michels","sequence":"additional","affiliation":[{"name":"Department of Pediatric Nephrology, Amalia Children\u2019s Hospital, Radboud University Medical Center, 6525 Nijmegen, The Netherlands"},{"name":"Department of Human Genetics, Radboud University Medical Center, 6525 Nijmegen, The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2026,7,29]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"785","DOI":"10.1038\/ni.1923","article-title":"Complement: A key system for immune surveillance and homeostasis","volume":"11","author":"Ricklin","year":"2010","journal-title":"Nat. Immunol."},{"key":"ref_2","doi-asserted-by":"crossref","unstructured":"Merle, N.S., Church, S.E., Fremeaux-Bacchi, V., and Roumenina, L.T. (2015). Complement system part I\u2014Molecular mechanisms of activation and regulation. Front. 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