Preprint
Monoclonal nephritic factors reveal insights into C3 convertase dynamics and dysregulation
bioRxiv
Cold Spring Harbor Laboratory Preprints
06/12/2026
DOI: 10.64898/2026.06.11.731599
PMCID: PMC13278002
PMID: 42327152
Abstract
C3- and C5-nephritic factors are potent but poorly understood autoantibodies that dysregulate complement convertases. To date, their underlying mechanisms of action, epitopes, and sequences remain unknown. To address this knowledge gap, we immune profiled B cells from a nephritic factor-positive C3 glomerulopathy patient and identified the first monoclonal C3- and C5-nephritic factors. We present the structure of a C3-nephritic factor bound to a C3 convertase with the convertase protease domain unexpectedly rotated and inhibited. This rotation advances our understanding of complement convertase progression and decay, explains disease-associated convertase variants, and reveals the molecular mechanism by which nephritic factors can either activate or inhibit convertase activity. We also detail heterogeneity within and between C3- and C5-nephritic factors in terms of convertase binding, stabilizing capacity, regulator inhibition, fluid-phase activation, and disease contribution. These findings improve stratification of patients with C3 glomerulopathy, redefine basic C3 convertase dynamics, and provide insights into antibody-mediated modulation of the complement system.
Details
- Title: Subtitle
- Monoclonal nephritic factors reveal insights into C3 convertase dynamics and dysregulation
- Creators
- Seth J. Welsh - University of IowaChristopher T. Culek - University of IowaZhen Xu - University of IowaHéctor Merinero - University of IowaJannik Sichau - Universität UlmDaniel Walls - University of IowaRenee Goodfellow - University of IowaDingwu Shao - University of IowaCobey Donelson - University of IowaKameron Kruger - University of IowaSarah Roberts - University of IowaNicole C. Meyer - University of IowaAngela F. M. Nelson - University of IowaAnna R. Carmen - University of IowaSydney S. Jellison - University of IowaStephanie N Cook - University of IowaMonica D. Hall - University of IowaRebecca Franklin - University of IowaTina Liu - University of Iowa, OtolaryngologyJill Hall - University of IowaLauren O. Fergus - University of IowaNicholas J Schnicker - University of IowaChristoph Q. Schmidt - Universität UlmYuzhou Zhang - University of IowaCarla M. Nester - University of IowaRichard J.H. Smith - University of Iowa
- Resource Type
- Preprint
- Publication Details
- bioRxiv
- DOI
- 10.64898/2026.06.11.731599
- PMID
- 42327152
- PMCID
- PMC13278002
- eISSN
- 2692-8205
- Publisher
- Cold Spring Harbor Laboratory Preprints
- Language
- English
- Date posted
- 06/12/2026
- Academic Unit
- Roy J. Carver Department of Biomedical Engineering; Molecular Physiology and Biophysics; Anatomy and Cell Biology; Nephrology, Dialysis and Transplantation; Stead Family Department of Pediatrics; Iowa Neuroscience Institute; Medicine Administration; Otolaryngology; Internal Medicine
- Record Identifier
- 9985175375902771
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