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The alternative pathway C3 convertase and glomerular deposits
1Division of Nephrology, Children's Hospital Medical Center, Cincinnati, OH 45229-3039, USA.
Insights
Excess complement C3 convertase, C3b,Bb, due to factor H dysfunction causes nephritis. This occurs in Marder disease, factor H deficiency, and specific types of membranoproliferative glomerulonephritis (MPGN).
Area of Science:
- Immunology
- Nephrology
- Complement System Biology
Background:
- Factor H dysfunction leads to excess alternative pathway C3 convertase (C3b,Bb), frequently causing nephritis.
- This condition is observed in Marder disease (factor H binding site defect), homozygous factor H deficiency, factor H inhibitors, and specific MPGN types.
Purpose of the Study:
- To investigate the relationship between excess complement convertase and glomerular deposits in various nephritic conditions.
- To analyze the correlation between complement levels and the presence/type of glomerular deposits in MPGN types II and III, factor H deficiency, and Marder disease.
Main Methods:
- Observational study analyzing clinical data and biopsy findings.
- Correlation of complement levels (hypocomplementemic vs. normocomplementemic) with the presence and location of glomerular deposits.
Main Results:
- In MPGN type II, subepithelial paramesangial deposits correlate with hypocomplementemia.
- MPGN type III shows paramesangial deposits with hypocomplementemia and subendothelial deposits only during hypocomplementemia.
- Paramesangial deposits are characteristic of factor H deficiency and Marder disease.
Conclusions:
- Excessive C3 convertase is linked to nephritis and specific glomerular deposition patterns.
- Variations in nephritis incidence, severity, and morphology may depend on convertase characteristics and C3 products.
Abstract:
Five conditions in which the alternative pathway C3 convertase, C3b,Bb, circulates in excess as a result of factor H dysfunction are frequently accompanied by nephritis. These convertase-related nephritides are seen in association with heterozygous absence of a binding site for factor H on C3b (Marder disease), homozygous factor H deficiency, circulating factor H inhibitor, and with the nephritic factors, one of the amplification loop and the other of the terminal pathway, found in membranoproliferative glomerulonephritis (MPGN) types II and III, respectively. Observations which relate convertase to glomerular deposits are: (1) in MPGN type II, subepithelial deposits on the paramesangial segments of the glomerular basement membrane are with high frequency present in patients hypocomplementemic at biopsy, but not in those normocomplementemic; (2) in MPGN type III paramesangial deposits are similarly found with hypocomplementemia but are present for up to 1 year after normocomplementemia is achieved; (3) in MPGN type III, subendothelial deposits are present only with hypocomplementemia. The principal deposits found in factor H deficiency and in Marder disease are also paramesangial. Differences in the incidence, severity, and morphology of the nephritides accompanying convertase in excess may relate to the characteristics of the circulating convertase and/or to the C3 conversion products formed by it.