Uncontrolled C3 activation causes membranoproliferative glomerulonephritis in mice deficient in complement factor H.
The alternative pathway of complement is activated continuously in vivo through the C3 'tick-over' pathway. 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 enzyme, and, together with factor I, mediates the proteolytic inactivation of C3b. Factor H deficiency, described in 29 individuals from 12 families and in pigs, allows unhindered activation of fluid-phase C3 and severe depletion of plasma C3 (ref. 11). Membranoproliferative glomerulonephritis (MPGN) occurs in factor H-deficient humans and pigs. 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.
Pickering
Matthew C
MC
Rheumatology Section, Faculty of Medicine, Imperial College, Hammersmith Campus, Du Cane Road, London W12 0NN, UK.
Cook
H Terence
HT
Warren
Joanna
J
Bygrave
Anne E
AE
Moss
Jill
J
Walport
Mark J
MJ
Botto
Marina
M
D000818:Animals; D003167:Complement Activation / Q000235:genetics*; D003176:Complement C3 / Q000276:immunology* / Q000378:metabolism; D003186:Complement C9 / Q000378:metabolism; D017242:Complement Factor H / Q000235:genetics* / Q000378:metabolism; D004195:Disease Models, Animal; D005260:Female; D005921:Glomerulonephritis / Q000235:genetics* / Q000503:physiopathology*; D007668:Kidney / Q000473:pathology / Q000648:ultrastructure; D008297:Male; D051379:Mice; D008815:Mice, Inbred Strains; D008817:Mice, Mutant Strains; D009154:Mutation
D003176:Complement C3; D003186:Complement C9; D017242:Complement Factor H