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Uncontrolled C3 activation causes membranoproliferative glomerulonephritis in mice deficient in complement factor H

Nature Genetics volume 31, pages 424–428 (2002)Cite this article

Abstract

The alternative pathway of complement is activated continuously in vivo through the C3 'tick-over' pathway1. This pathway is triggered by the hydrolysis of C3, resulting in the formation of C3 convertase. This, in turn, generates C3b, which mediates many of the biological functions of complement. Factor H, the main regulator of this activation, prevents formation and promotes dissociation of the C3 convertase enzyme2,3, and, together with factor I, mediates the proteolytic inactivation of C3b4. Factor H deficiency, described in 29 individuals from 12 families5,6,7,8,9,10,11,12,13,14 and in pigs15, allows unhindered activation of fluid-phase C3 and severe depletion of plasma C3 (ref. 11). Membranoproliferative glomerulonephritis (MPGN) occurs in factor H–deficient humans6,12,13 and pigs15. Although MPGN has been reported in other conditions in which uncontrolled activation of C3 occurs, the role of C3 dysregulation in the pathogenesis of MPGN is not understood. Here we show that mice deficient in factor H (Cfh−/− mice) develop MPGN spontaneously and are hypersensitive to developing renal injury caused by immune complexes. Introducing a second mutation in the gene encoding complement factor B, which prevents C3 turnover in vivo, obviates the phenotype of Cfh−/− mice. Thus, uncontrolled C3 activation in vivo is essential for the development of MPGN associated with deficiency of factor H.

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Figure 1: Targeted disruption of the murine factor H gene.
Figure 2: Renal pathology in Cfh−/− mice.
Figure 3: Immunoelectron microscopy showing subendothelial capillary wall deposits stained for C3 and C9 in 2-month Cfh−/− mice.
Figure 4: Glomerular C3 deposition and subendothelial electron-dense deposits do not develop in 2-month Cfh−/−Bf−/− mice.

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Acknowledgements

We thank M. Lewis and I. Shore for processing the samples for histology and electron microscopy; J. Meek for the serum albumin and creatinine analysis; R.B. Sim for help with western blotting of factor H; H. Colten for factor B–deficient mice; B.P. Morgan for the antibody against C9; and M.R. Daha for the antibody against factor H. M.C.P. is funded by the Arthritis Research Campaign. This work was also supported by the Wellcome trust.

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  1. Rheumatology Section, Faculty of Medicine, Imperial College, Hammersmith Campus, Du Cane Road, London, W12 0NN, UK

    Matthew C. Pickering, Joanna Warren, Anne E. Bygrave, Mark J. Walport & Marina Botto

  2. Department of Histopathology, Faculty of Medicine, Imperial College, Hammersmith Campus, Du Cane Road, London, W12 0NN, UK

    H. Terence Cook

  3. Department of Histopathology, Electron Microscopy Unit, Charing Cross Hospital, Fulham Palace Road, London, W6 8RF, UK

    Jill Moss

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Correspondence to Marina Botto.

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Pickering, M., Cook, H., Warren, J. et al. Uncontrolled C3 activation causes membranoproliferative glomerulonephritis in mice deficient in complement factor H. Nat Genet 31, 424–428 (2002). https://doi.org/10.1038/ng912

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