title: Factor I is required for the development of membranoproliferative glomerulonephritis in factor H-deficient mice.
abstract: The inflammatory kidney disease membranoproliferative glomerulonephritis type II (MPGN2) is associated with dysregulation of the alternative pathway of complement activation. MPGN2 is characterized by the presence of complement C3 along the glomerular basement membrane (GBM). Spontaneous activation of C3 through the alternative pathway is regulated by 2 plasma proteins, factor H and factor I. Deficiency of either of these regulators results in uncontrolled C3 activation, although the breakdown of activated C3 is dependent on factor I. Deficiency of factor H, but not factor I, is associated with MPGN2 in humans, pigs, and mice. To explain this discordance, mice with single or combined deficiencies of these factors were studied. MPGN2 did not develop in mice with combined factor H and I deficiency or in mice deficient in factor I alone. However, administration of a source of factor I to mice with combined factor H and factor I deficiency triggered both activated C3 fragments in plasma and GBM C3 deposition. Mouse renal transplant studies demonstrated that C3 deposited along the GBM was derived from plasma. Together, these findings provide what we believe to be the first evidence that factor I-mediated generation of activated C3 fragments in the circulation is a critical determinant for the development of MPGN2 associated with factor H deficiency.
authors.affiliation: Molecular Genetics and Rheumatology Section, Faculty of Medicine, Imperial College, Hammersmith Campus, London, United Kingdom.
authors.forename: Kirsten L
authors.initials: KL
authors.lastname: Rose
authors.forename: Danielle
authors.initials: D
authors.lastname: Paixao-Cavalcante
authors.forename: Jennifer
authors.initials: J
authors.lastname: Fish
authors.forename: Anthony P
authors.initials: AP
authors.lastname: Manderson
authors.forename: Talat H
authors.initials: TH
authors.lastname: Malik
authors.forename: Anne E
authors.initials: AE
authors.lastname: Bygrave
authors.forename: Tao
authors.initials: T
authors.lastname: Lin
authors.forename: Steven H
authors.initials: SH
authors.lastname: Sacks
authors.forename: Mark J
authors.initials: MJ
authors.lastname: Walport
authors.forename: H Terence
authors.initials: HT
authors.lastname: Cook
authors.forename: Marina
authors.initials: M
authors.lastname: Botto
authors.forename: Matthew C
authors.initials: MC
authors.lastname: Pickering
mesh_terms: D000818:Animals; D003176:Complement C3 / Q000032:analysis / Q000378:metabolism*; D017242:Complement Factor H / Q000008:administration & dosage / Q000172:deficiency* / Q000235:genetics; D017244:Complement Factor I / Q000008:administration & dosage / Q000235:genetics / Q000502:physiology*; D015432:Glomerulonephritis, Membranoproliferative / Q000097:blood / Q000235:genetics* / Q000276:immunology; D051379:Mice; D008817:Mice, Mutant Strains
chemical_list: D003176:Complement C3; D017242:Complement Factor H; D017244:Complement Factor I