Background
C3 glomerulopathy (C3G) defines a group of rare complement-mediated kidney diseases with a shared underlying pathophysiology: dysregulation of complement in the fluid phase and glomerular microenvironment. Dysregulation can be driven by autoantibodies to C3 and C5 convertases.
Study Design
Case series
Setting & Participants
168 C3G patients (dense deposit disease, 68; C3 glumerulonephritis, 100) selected from our C3G bio-bank.
Outcomes
Patient-purified IgGs were tested for C4 nephritic factors (C4Nefs). These autoantibodies recognize C4b2a, the C3 convertase of the classical pathway of complement.
Measurements
C4Nefs were detected using a modified hemolytic assay.
Results
C4Nefs were identified in 5 patients, 4 of whom had C3 glomerulonephritis. The C4Nefs were associated with dysregulation of C3 and C5 convertases and they appear to stabilize these convertases in a dose-dependent manner. The C4Nefs also appear to protect C4b2a from decay mediated by soluble CR1 and C4 binding protein (C4BP). The stabilizing activity of the autoantibodies was further demonstrated by using heat treatment to inactivate complement. C4Nefs were not detected in 150 patients with another complement-mediated kidney disease, atypical hemolytic uremic syndrome. They were also absent in 300 apparently healthy controls.
Limitations
In addition to C4Nefs, two patients had positive findings for other autoantibodies: one patient also had autoantibodies to factor H; the other patient also had autoantibodies to C3bBb (C3Nefs).
Conclusions
The finding of C4Nefs in a small percentage of C3G patients highlights the challenge in identifying autoantibodies that drive complement dysregulation and underscores the complexity of the autoantibody repertoire that can be identified in these patients.
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