Monoclonal nephritic factors reveal insights into C3 convertase dynamics and dysregulation
Year: 2026
Type: preprint
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.
Authors: Seth J. Welsh, Christopher T. Culek, Zhen Xu, Héctor Merinero, Jannik Sichau, Daniel Walls, Renee Goodfellow, Dingwu Shao, Cobey Donelson, Kameron Kruger, Sarah Roberts, Nicole C. Meyer, Angela F. M. Nelson, Anna R. Carmen, Sydney S. Jellison, Stephanie N Cook, Monica D. Hall, Rebecca Franklin, Tina Liu, Jill Hall, Lauren O. Fergus, Nicholas J Schnicker, Christoph Q. Schmidt, Yuzhou Zhang, Carla M. Nester, Richard J.H. Smith
Language: English
Subfield: Immunology
Field: Immunology and Microbiology
Domain: Life Sciences
Open Access status: green
OpenAlex ID: W7164556390