Researchers Identify First Monoclonal Nephritic Factors, Revealing How Autoantibodies Dysregulate Complement System
Researchers have identified the first monoclonal C3- and C5-nephritic factors by immune profiling B cells from a patient with C3 glomerulopathy, and determined the structure of a C3-nephritic factor bound to a complement convertase. The structural analysis revealed an unexpectedly rotated protease domain, offering new insight into how these autoantibodies can either activate or inhibit convertase activity. These findings could improve patient stratification in C3 glomerulopathy and reshape understanding of complement system regulation.
C3- and C5-nephritic factors are autoantibodies known to dysregulate complement convertases—enzymes central to immune defense—but their mechanisms, epitopes, and sequences have remained poorly characterized until now. By immune profiling B cells from a nephritic factor-positive C3 glomerulopathy patient, the researchers isolated the first monoclonal versions of both C3- and C5-nephritic factors. Cryo-structural analysis of a C3-nephritic factor bound to a C3 convertase revealed that the convertase's protease domain adopts an unexpected rotated conformation that inhibits its activity, a finding that reframes current models of convertase progression and decay. This structural insight also helps explain why certain disease-associated convertase variants behave differently and clarifies the dual capacity of nephritic factors to either stabilize or inhibit convertase function depending on context. The study further documents heterogeneity among nephritic factors in terms of convertase binding, regulator inhibition, fluid-phase activation, and disease contribution. Collectively, these results provide a molecular framework for understanding antibody-mediated complement dysregulation and offer potential tools for better stratifying patients with C3 glomerulopathy.
What's missing
As a preprint posted on bioRxiv, this work has not yet undergone formal peer review, so the structural interpretations and clinical implications should be considered preliminary. The study is based on B cells from a single patient, which limits generalizability; it remains unclear whether the identified monoclonal nephritic factors are representative of the broader patient population.
What different sources said
- bioRxivCenter
Monoclonal nephritic factors reveal insights into C3 convertase dynamics and dysregulation
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