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Both Complement and IgG Fc Receptors Are Required for Development of Attenuated Antiglomerular Basement Membrane Nephritis in Mice¹

Marielle A. Otten^2,*, Tom W. L. Groeneveld^2,*, Roelof Flierman^*, Maria Pia Rastaldi, Leendert A. Trouw, Maria C. Faber-Krol^*, Annemieke Visser^*, Maria C. Essers^*, Jill Claassens, J. Sjef Verbeek, Cees van Kooten^*, Anja Roos^*,¶ and Mohamed R. Daha^3,*

^* Department of Nephrology, Leiden University Medical Center, Leiden, The Netherlands; Renal Research Laboratory, Fondazione Istituto Di Ricovero e Cura a Carattere Scientifico Ospedale Maggiore Policlinico and Fondazione D’Amico per la Ricerca sulle Malattie Renali, Milano, Italy; and Department of Rheumatology, Department of Human Genetics, and ^¶ Department of Clinical Chemistry, LUMC, Leiden, The Netherlands

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 FcR or complement, depending on the experimental model used. In this study, we provide evidence that both FcR 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--chain^–/– mice and reduced in C3^–/– mice, a role for both FcR 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 FcR 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.

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ This work was supported by NWO/Zon-MW (901-12-095) and the European Union (LSHB-CT-2004-504761).

² M.A.O. and T.W.L.G. contributed equally to this study.

³ Address correspondence and reprint requests to Prof. Dr. M. R. Daha, Department of Nephrology, LUMC, Albinusdreef 2, 2333 ZA, Leiden, The Netherlands. E-mail address: m.r.daha{at}lumc.nl

⁴ Abbreviations used in this paper: GBM, glomerular basement membrane; PAS, periodic acid-Schiff; WT, wild type; DIG, digitonin.