C3-Glomerulopathy Autoantibodies Mediate Distinct Effects on Complement C3- and C5-Convertases.

Area of Science:

• Immunology
• Nephrology
• Complement System Biology

Background:

• C3 glomerulopathy (C3G) is a severe kidney disease stemming from dysregulation of the alternative complement pathway.
• Pathogenesis is complex, involving both autoimmune and genetic factors.

Purpose of the Study:

• To characterize IgG autoantibodies in patients with autoimmune C3G.
• To investigate the functional consequences of these autoantibodies on complement convertases.

Main Methods:

• Characterization of IgG autoantibodies from 33 C3G patients.
• Assessment of C3 and C5 convertase binding and stabilization.
• Evaluation of C3a and C5a generation.
• C3Nef assay and hemolytic assays.

Main Results:

• Two groups of C3-convertase binding autoantibodies were identified: strong (Group 1) and weak (Group 2).
• Group 1 antibodies stabilized C3-convertase, protected it from Factor H, and induced C3a release.
• Both groups bound C5-convertase and induced C5a generation, inhibited by Eculizumab.
• C3Nef was present in 19 patients, independent of C3-convertase binding profile.

Conclusions:

• Autoimmune C3G exhibits heterogeneity based on autoantibody profiles, with Group 1 acting as C3Nef/C5Nef and Group 2 as predominantly C5Nef.
• Current diagnostic methods may not identify all autoimmune forms of C3G.
• Enhanced autoantibody testing is crucial for accurate diagnosis and understanding of C3G pathogenesis.