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Modeling how CD46 deficiency predisposes to atypical hemolytic uremic syndrome
M Kathryn Liszewski1, Marilyn K Leung, Barbara Schraml
1Washington University School of Medicine, 660 South Euclid Avenue, Campus Box 8045, St. Louis, MO 63110, USA.
Insights
Mutations in membrane cofactor protein (MCP) can cause atypical hemolytic uremic syndrome (aHUS). Reduced MCP levels or dysfunctional MCP mutants impair complement regulation, implicating the alternative pathway in aHUS.
Area of Science:
- Immunology
- Complement System Biology
Background:
- Atypical hemolytic uremic syndrome (aHUS) is linked to mutations in complement regulatory proteins.
- Factor H, Factor I, and membrane cofactor protein (MCP; CD46) mutations are found in ~50% of aHUS patients.
- Decay accelerating factor (DAF; CD55), a related regulator, lacks known aHUS association.
Purpose of the Study:
- To compare the complement regulatory functions of MCP and DAF.
- To investigate how MCP alterations contribute to complement dysregulation in aHUS.
Main Methods:
- Utilized a Chinese hamster ovary (CHO) cell model system for complement activation.
- Assessed C3b deposition and alternative/classical pathway inhibition by MCP and DAF.
- Analyzed the impact of reduced wild-type MCP levels and a specific MCP mutant (S206P) on complement regulation.
Main Results:
- Both MCP and DAF inhibited alternative pathway C3b deposition.
- DAF inhibited the classical pathway, whereas MCP did not.
- Reduced MCP expression levels decreased alternative pathway inhibition efficiency.
- A dysfunctional MCP mutant (S206P) failed to protect against C3b amplification, even at high expression levels.
Conclusions:
- Appropriate expression levels of MCP are crucial for effective complement regulation.
- The alternative complement pathway is implicated in aHUS pathogenesis.
- Dysfunctional MCP variants contribute to complement dysregulation in aHUS.
Abstract:
Mutations in complement regulatory proteins predispose to the development of aHUS. Approximately 50% of patients bear a mutation in one of three complement control proteins, factor H, factor I, or membrane cofactor protein (MCP; CD46). Another membrane regulator that is closely related to MCP, decay accelerating factor (DAF; CD55) thus far has shown no association with aHUS and continues to be investigated. The goal of this study was to compare the regulatory profile of MCP and DAF and to assess how alterations in MCP predispose to complement dysregulation. We employed a model system of complement activation on Chinese hamster ovary (CHO) cell transfectants. The four regularly expressed isoforms of MCP and DAF inhibited C3b deposition by the alternative pathway. DAF, but not MCP, inhibited the classical pathway. Most patients with MCP-aHUS are heterozygous and express only 25-50% of the wild-type protein. We, therefore, analyzed the effect of reduced levels of wild-type MCP and found that cells with lowered expression levels were less efficient in inhibiting alternative pathway activation. Further, a dysfunctional MCP mutant, expressed at normal levels and identified in five patients with aHUS (S206P), failed to protect against C3b amplification on CHO cells, even if expression levels were increased 10-fold. Our results add new information relative to the necessity for appropriate expression levels of MCP and further implicate the alternative pathway in disease processes such as aHUS.
