Factor H facilitates the clearance of GBM bound iC3b by controlling C3 activation in fluid phase.
Dense deposit disease (DDD) is strongly associated with the uncontrolled activation of the complement alternative pathway. Factor H (CFH)-deficient (Cfh(-/-)) mice spontaneously develop C3 deposition along the glomerular basement membrane (GBM) with subsequent development of glomerulonephritis with features of DDD, a lesion dependent on C3 activation. In order to understand the role of CFH in preventing renal damage associated with the dysregulation of the alternative pathway we administered purified mouse CFH (mCFH) to Cfh(-/-) mice. 24h following the administration of mCFH we observed an increase in plasma C3 levels with presence of intact C3 in circulation showing that mCFH restored control of C3 activation in fluid phase. mCFH resulted in the reduction of iC3b deposition along the GBM. The exogenous mCFH was readily detectable in plasma but critically not in association with C3 along the GBM. Thus, the reduction in GBM C3 was dependent on the ability of mCFH to regulate C3 activation in plasma. Western blot analysis of glomeruli from Cfh(-/-) mice demonstrated the presence of iC3b. Our data show that the C3 along the GBM in Cfh(-/-) mice is the C3 fragment iC3b and that this is derived from plasma C3 activation. The implication is that successful therapy of DDD is likely to be achieved by therapies that inhibit C3 turnover in plasma.
Paixão-Cavalcante
Danielle
D
Molecular Genetics and Rheumatology Section, Faculty of Medicine, Imperial College, Hammersmith Campus, Du Cane Road, London, W12 0NN, UK.
Hanson
Steven
S
Botto
Marina
M
Cook
H Terence
HT
Pickering
Matthew C
MC
D000818:Animals; D039481:CD11b Antigen / Q000276:immunology; D003167:Complement Activation / Q000187:drug effects / Q000276:immunology*; D003176:Complement C3 / Q000096:biosynthesis; D003179:Complement C3b / Q000276:immunology*; D017242:Complement Factor H / Q000008:administration & dosage / Q000172:deficiency / Q000276:immunology* / Q000494:pharmacology; D050533:Glomerular Basement Membrane / Q000187:drug effects / Q000276:immunology*; D006801:Humans; D007668:Kidney / Q000187:drug effects / Q000276:immunology; D051379:Mice; D009504:Neutrophils / Q000166:cytology / Q000187:drug effects / Q000276:immunology; D011485:Protein Binding / Q000187:drug effects; D021381:Protein Transport / Q000187:drug effects
D039481:CD11b Antigen; D003176:Complement C3; D003179:Complement C3b; D017242:Complement Factor H