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Uncontrolled C3 activation causes membranoproliferative glomerulonephritis in mice deficient in complement factor H
Matthew C Pickering1, H Terence Cook, Joanna Warren
1Rheumatology Section, Faculty of Medicine, Imperial College, Hammersmith Campus, Du Cane Road, London W12 0NN, UK.
Nature Genetics
|July 2, 2002
Summary
Factor H deficiency causes uncontrolled complement C3 activation, leading to severe kidney disease called membranoproliferative glomerulonephritis (MPGN). Blocking C3 activation prevents MPGN in these mice, highlighting C3
Area of Science:
- Immunology
- Nephrology
- Complement System Biology
Background:
- The alternative pathway of complement is constitutively active via C3 'tick-over'.
- Factor H is the primary regulator of complement activation, preventing C3 convertase formation and promoting C3b inactivation.
- Factor H deficiency leads to unhindered C3 activation, C3 depletion, and membranoproliferative glomerulonephritis (MPGN).
Purpose of the Study:
- To investigate the role of complement C3 dysregulation in the pathogenesis of MPGN in factor H deficiency.
- To determine if uncontrolled C3 activation is essential for MPGN development in the absence of factor H.
Main Methods:
- Generation and analysis of mice deficient in factor H (Cfh(-/-) mice).
- Assessment of renal injury, specifically MPGN, in Cfh(-/-) mice.
- Introduction of a mutation in complement factor B to prevent C3 turnover in Cfh(-/-) mice and evaluate its effect on MPGN.
Main Results:
- Cfh(-/-) mice spontaneously developed MPGN and showed hypersensitivity to immune complex-induced renal injury.
- Preventing C3 turnover by mutating complement factor B obviated the MPGN phenotype in Cfh(-/-) mice.
- Uncontrolled C3 activation was directly linked to the development of MPGN in factor H-deficient mice.
Conclusions:
- Uncontrolled in vivo complement C3 activation is essential for the development of MPGN associated with factor H deficiency.
- This study elucidates the critical role of C3 dysregulation in the pathogenesis of factor H-related kidney disease.