Characterizing Properdin-Inhibited C3 Nephritic Factors in Patients with Complement-Mediated Kidney Diseases

Area of Science:

• Immunology
• Nephrology
• Complement System Biology

Background:

• C3 glomerulopathy (C3G) and immune complex-mediated membranoproliferative glomerulonephritis (IC-MPGN) are severe kidney diseases driven by complement system dysregulation.
• C3 nephritic factors (C3NeFs) are autoantibodies that stabilize the alternative pathway (AP) C3 convertase, contributing to these diseases.
• Previous research has identified properdin-dependent and independent C3NeFs, but a distinct subset remained uncharacterized.

Purpose of the Study:

• To investigate a novel subset of C3NeFs that are exclusively active in the absence of properdin, termed properdin-inhibited C3NeFs.
• To characterize the activity and prevalence of these properdin-inhibited C3NeFs in patients with C3G and IC-MPGN.

Main Methods:

• Utilized a two-step hemolytic AP convertase activity assay with a properdin inhibitor (Salp20) to assess convertase stabilization in patient serum.
• Employed purified patient immunoglobulins (Igs) in properdin-depleted serum to confirm findings.
• Conducted an ELISA-based C3bBb binding assay to evaluate C3NeF binding to the AP C3 convertase.

Main Results:

• Properdin-inhibited C3NeF activity was detected in 7/16 patients but only 1/23 healthy controls, indicated by convertase stabilization upon properdin inhibition.
• Purified patient Igs confirmed these findings, showing increased convertase binding in 6/7 patients with properdin-inhibited C3NeFs, which decreased with properdin addition.
• Complement and properdin levels did not significantly differ between patients with and without properdin-inhibited C3NeFs.

Conclusions:

• The study provides evidence for the existence of properdin-inhibited C3NeFs, expanding the known functional heterogeneity of these autoantibodies.
• The findings suggest that properdin-inhibited C3NeFs may not be functionally relevant under normal physiological conditions.
• The presence of properdin-inhibited C3NeFs could have significant implications for complement-targeted therapies, particularly those involving properdin inhibition, due to potential unintended effects.