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An inherited defect in the C3 convertase, C3b,Bb, associated with glomerulonephritis
Insights
A defect in controlling the serum complement system
Area of Science:
- Immunology
- Nephrology
- Genetics
Background:
- The serum complement system is crucial for innate immunity, with its amplification C3 convertase (C3b,Bb) playing a key role.
- Dysregulation of the complement system is implicated in various kidney diseases, including glomerulonephritis.
- Proper functioning of complement regulatory proteins, Factor H and Factor I, is essential for preventing uncontrolled complement activation.
Observation:
- Five family members across three generations exhibited defective control of the C3b,Bb amplification convertase.
- Affected individuals presented with low serum concentrations of C3 and Factor B, but normal levels of Factors H and I.
- Serum from affected individuals showed enhanced C3 conversion upon incubation, further accelerated by increased magnesium levels.
Findings:
- The amplification convertase in affected family members demonstrated increased resistance to inhibition by Factor H.
- Addition of purified normal C3, but not the propositus's C3, reduced the Factor H requirement for inhibition.
- Affected individuals are postulated to be heterozygous for a gene encoding an abnormal C3 variant.
Implications:
- The abnormal C3 variant likely confers resistance to Factor H, leading to complement dysregulation.
- This defect is potentially nephritogenic, contributing to the development of glomerulonephritis in affected family members.
- Understanding this complement regulatory defect may offer insights into the pathogenesis of specific glomerulonephritides.
Abstract:
The control of the amplification C3 convertase, C3b,Bb, of the serum complement system has been found to be defective in five members of a family spanning three generations. One of the five has membranoproliferative glomerulonephritis (MPGN) type III and another has mild idiopathic rapidly progressive glomerulonephritis. The defect is manifested by low serum concentrations of C3 and usually factor B with normal levels of the proteins which control the convertase, H and I. C3 nephritic factor (C3NeF) was not demonstrable. Enhanced C3 conversion was produced by the incubation of their serum at 37 degrees C for 30 min. This conversion was further accelerated by incubation after increasing the serum magnesium concentration by increments ranging from 0.25 to 1.9 mM. Incremental additions of H to serum depleted of H indicated that the amplification convertase of affected family members required more H for its inhibition than did that of normal subjects. This requirement was reduced by the addition of purified normal C3 but not by the addition of purified C3 of the propositus. It is postulated that affected family members are heterozygous for a gene producing an abnormal C3 which, as a constituent of the amplification convertase, C3b,Bb, confers resistance to H. Investigation of this apparently nephritogenic defect may provide insight into the pathogenesis of these glomerulonephritides.