Both complement and IgG fc receptors are required for development of attenuated antiglomerular basement membrane nephritis in mice.
To elucidate the mechanisms of glomerulonephritis, including Goodpasture's syndrome, mouse models are used that use heterologous Abs against the glomerular basement membrane (GBM) with or without preimmunization with foreign IgG from the same species. These studies have revealed the requirement of either FcgammaR or complement, depending on the experimental model used. In this study, we provide evidence that both FcgammaR and complement are obligatory for a full-blown inflammation in a novel attenuated passive model of anti-GBM disease. We demonstrate that administration of subnephritogenic doses of rabbit anti-GBM Abs followed by a fixed dose of mouse mAbs to rabbit IgG, allowing timing and dosing for the induction of glomerulonephritis, resulted in reproducible complement activation via the classical pathway of complement and albuminuria in wild-type mice. Because albuminuria was absent in FcR-gamma-chain(-/-) mice and reduced in C3(-/-) mice, a role for both FcgammaR and complement is postulated. Because C1q(-/-) and C4(-/-) mice lacking a functional classical and lectin pathway did develop albuminuria, we suggest involvement of the alternative pathway of complement. Anti-GBM glomerulonephritis occurs acutely following the administration of mouse anti-rabbit IgG, and proceeds in a chronic fashion dependent on both FcgammaR and complement. This novel attenuated model allows elucidating the relative contribution of different mediator systems of the immune system to the development of renal injury, and also provides a platform for the assessment of different treatment protocols and evaluation of drugs that ultimately may be beneficial for the treatment of anti-GBM mediated glomerulonephritides.
Otten
Marielle A
MA
Department of Nephrology, Leiden University Medical Center, Leiden, The Netherlands.
Groeneveld
Tom W L
TW
Flierman
Roelof
R
Rastaldi
Maria Pia
MP
Trouw
Leendert A
LA
Faber-Krol
Maria C
MC
Visser
Annemieke
A
Essers
Maria C
MC
Claassens
Jill
J
Verbeek
J Sjef
JS
van Kooten
Cees
C
Roos
Anja
A
Daha
Mohamed R
MR
D000419:Albuminuria / Q000209:etiology; D000818:Animals; D019867:Anti-Glomerular Basement Membrane Disease / Q000209:etiology / Q000276:immunology* / Q000473:pathology; D001323:Autoantibodies; D003167:Complement Activation; D007074:Immunoglobulin G / Q000008:administration & dosage; D007249:Inflammation; D051379:Mice; D009393:Nephritis / Q000276:immunology* / Q000473:pathology; D011951:Receptors, Complement / Q000502:physiology*; D017452:Receptors, IgG / Q000502:physiology*
D001323:Autoantibodies; D007074:Immunoglobulin G; D011951:Receptors, Complement; D017452:Receptors, IgG; C051951:antiglomerular basement membrane antibody