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Glomerular C3c localization indicates ongoing immune deposit formation and complement activation in experimental
M Schulze1, C J Pruchno, M Burns
1Division of Nephrology, University of Washington, Seattle 98195.
Insights
Glomerular C3c deposits clear within 24 hours after complement activation stops in glomerulonephritis models. This rapid clearance of C3c indicates recent complement activation, aiding in diagnosing kidney disease.
Area of Science:
- Nephrology
- Immunology
- Biochemistry
Background:
- Antibody-mediated glomerular diseases feature C3 deposits.
- Factor I degrades C3b to C3c and C3d.
- Kinetics of C3b degradation in glomerulonephritis are undefined.
Purpose of the Study:
- Define the kinetics of C3b degradation in experimental glomerulonephritis.
- Assess the clearance rate of C3c and C3d deposits in glomeruli.
Main Methods:
- Studied three models of complement-dependent glomerulonephritis.
- Halted C3b deposition using cobra venom factor.
- Measured C3c and C3d disappearance using specific antibodies and quantitative fluorescence densitometry.
Main Results:
- Glomerular C3c deposits decreased by over 85% within 24 hours across all models.
- C3c clearance was independent of deposit formation site or mechanism.
- C3d deposits remained even without ongoing complement activation.
- C3c clearance paralleled normalization of urinary C5b-9 excretion in passive Heymann nephritis.
Conclusions:
- Glomerular C3c deposits are cleared within 24 hours after complement activation ceases.
- Positive C3c staining signifies recent complement activation and potential immune deposit formation.
Abstract:
In antibody-mediated glomerular disease, deposits of C3 (C3b) are common and are degraded by factor I to C3c and C3d. However, the kinetics of C3b degradation in glomerulonephritis have not been defined. To do this, we studied three models of complement-dependent glomerulonephritis with established C3 deposits (passive Heymann nephritis, cationized immunoglobulin G membranous nephropathy, and concanavalin A-anticoncanavalin A glomerulonephritis). C3b deposition was halted by administration of cobra venom factor, and the disappearance of C3c and C3d from glomeruli was measured with specific antibodies and quantitative fluorescence densitometry. Results showed that C3c deposits were reduced by over 85% within 24 hours in all three models. C3c clearance was unaffected by site or mechanism of deposit formation. C3d deposits persisted despite lack of ongoing complement activation. In passive Heymann nephritis when disease activity was monitored by urinary C5b-9 excretion, C3c was cleared in parallel with return of urine C5b-9 excretion to normal values. We conclude that glomerular deposits of C3c are cleared within 24 hours of cessation of complement activation. Positive staining for C3 utilizing antibody specific for the C3c portion documents recent complement activation usually reflecting new immune deposit formation.