Defining Nephritic Factors as Diverse Drivers of Systemic Complement Dysregulation in C3 Glomerulopathy

Area of Science:

• Nephrology
• Immunology
• Complement System Biology

Background:

• C3 glomerulopathy (C3G) is a rare kidney disease caused by complement C3 deposition in the glomerular basement membrane.
• Genetic variations and autoantibodies against complement proteins are implicated in C3G pathogenesis, but disease heterogeneity complicates characterization.

Purpose of the Study:

• To define C3G disease profiles based on drivers, biomarkers, and age.
• To correlate in vitro autoantibody function tests with in vivo complement dysregulation.
• To assess the association between autoantibody function and C3G progression.

Main Methods:

• Retrospective analysis of the Molecular Otolaryngology and Renal Research Laboratories C3G cohort.
• Integration of complement biomarker testing and in vitro autoantibody function assays.
• Evaluation of correlations between autoantibody-mediated convertase stabilization and systemic complement biomarkers.

Main Results:

• Autoantibodies against complement proteins were identified as disease drivers in 48% of C3G patients.
• A strong correlation was observed between in vitro autoantibody function and in vivo complement dysregulation.
• The degree of autoantibody stabilization capacity predicted poorer renal function in C3G patients.

Conclusions:

• Complement autoantibodies are significant drivers of systemic complement dysregulation in approximately 50% of C3G cases.
• This study reinforces the role of autoantibodies in C3G pathogenesis and renal damage.
• Further research is needed to identify novel drivers of C3G, especially in patients without identified genetic or acquired causes.