Murine Membranous Nephropathy: Immunization with alpha 3(IV) Collagen Fragment Induces Subepithelial Immune Complexes and Fc gamma R-Independent Nephrotic Syndrome

• Published in: The Journal of immunology (1950) Vol. 188; no. 7; pp. 3268 - 3277
• Main Authors: Zhang, Jun-Jun, Malekpour, Mahdi, Luo, Wentian, Ge, Linna, Olaru, Florina, Wang, Xu-Ping, Bah, Maimouna, Sado, Yoshikazu, Heidet, Laurence, Kleinau, Sandra, Fogo, Agnes B, Borza, Dorin-Bogdan
• Format: Journal Article
• Language: English
• Published: 01-04-2012
• ISSN: 0022-1767; 1550-6606
• DOI: 10.4049/jimmunol.1103368

Membranous nephropathy (MN) is a leading cause of nephrotic syndrome in adults and a significant cause of end-stage renal disease, yet current therapies are nonspecific, toxic, and often ineffective. The development of novel targeted therapies requires a detailed understanding of the pathogenic mechanisms, but progress is hampered by the lack of a robust mouse model of disease. We report that DBA/1 mice as well as congenic Fc gamma RIII-/- and FcR gamma -/- mice immunized with a fragment of alpha 3(IV) collagen developed massive albuminuria and nephrotic syndrome, because of subepithelial deposits of mouse IgG and C3 with corresponding basement membrane reaction and podocyte foot process effacement. The clinical presentation and histopathologic findings were characteristic of MN. Although immunized mice produced genuine anti- alpha 3NC1 autoantibodies that bound to kidney and lung basement membranes, neither crescentic glomerulonephritis nor alveolitis ensued, likely because of the predominance of mouse IgG1 over IgG2a and IgG2b autoantibodies. The ablation of activating IgG Fc receptors did not ameliorate injury, implicating subepithelial deposition of immune complexes and consequent complement activation as a major effector pathway. We have thus established an active model of murine MN. This model, leveraged by the availability of genetically engineered mice and mouse-specific reagents, will be instrumental in studying the pathogenesis of MN and evaluating the efficacy of novel experimental therapies.