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A novel C4 variant was observed in patients with renal insufficiency, appearing acquired rather than inherited. This finding suggests potential links between uremia and C4 phenotype alterations, impacting glomerulonephritis research.
Area of Science:
- Immunogenetics
- Nephrology
Background:
- The major histocompatibility complex (MHC)-linked complotype region contains alleles for B, C2, and C4 loci, closely associated with HLA-DR on chromosome 6.
- The C4A and C4B loci are duplicated and highly polymorphic, playing a crucial role in immune responses.
Purpose of the Study:
- To investigate a C4 variant observed in patients with renal insufficiency.
- To determine if the observed C4 variant is inherited or acquired, particularly in the context of membranoproliferative glomerulonephritis.
Main Methods:
- Electrophoretic analysis, including immunofixation electrophoresis and C4-specific hemolytic overlay, was used to characterize the C4 variant.
- Complotype and HLA typing were performed on families of affected patients.
- Sodium dodecyl sulfate-polyacrylamide gel electrophoresis under reducing conditions analyzed C4 alpha chain molecular masses.
Main Results:
- A C4 variant with electrophoretic mobility between C4B2 and C4B3 was identified in seven patients with renal insufficiency.
- Family studies indicated the variant was not inherited, suggesting an acquired alteration.
- The C4 variant appeared in plasma after the onset of uremia and could not be replicated in vitro in normal plasma.
Conclusions:
- The observed C4 variant is likely acquired in the presence of uremia, not a genetic trait.
- This acquired C4 alteration may be related to the C4B2.9 allele previously associated with glomerulonephritis.
- Distinguishing between genetic and acquired C4 alterations through family studies is essential for accurate phenotype interpretation.
Abstract:
The major histocompatibility complex (MHC)-linked complotype region includes alleles for B, C2, and C4 loci. These loci are closely linked to each other and to HLA-DR on chromosome 6. The duplicated C4 loci, C4A and B, are especially polymorphic. In seven patients with renal insufficiency, we observed a C4 variant with electrophoretic mobility between C4B2 and C4B3. Four of these patients were detected during a study of MHC markers in membranoproliferative glomerulonephritis. Complete complotype and HLA data from families of five of the seven patients demonstrated that the variant was not inherited. The pattern was revealed by immunofixation electrophoresis and also by C4-specific hemolytic overlay. In serial plasma specimens taken from one patient, the C4 variant appeared only after the patient became uremic. However, the variant could not be produced in normal plasma after incubation with C4-depleted uremic plasma. Sodium dodecyl sulfate-polyacrylamide gel electrophoresis under reducing conditions of immunoprecipitated C4 from these patients showed C4A and C4B alpha chains of normal molecular mass; incompletely processed forms of C4 were not observed. We believe that this variant is probably acquired in the presence of uremia and may represent the C4B2.9 allele found by Wank and co-workers in many patients with glomerulonephritis. Family studies are mandatory to distinguish genetic variants from acquired alterations in the C4 phenotype.