Pathology and protection in nephrotoxic nephritis is determined by selective engagement of specific Fc receptors

Introduction of heterologous anti-glomerular basement membrane antiserum (nephrotoxic serum, NTS) into presensitized mice triggers the production of IgG anti-NTS antibodies that are predominantly IgG2b and the glomerular deposition of pathogenic immune complexes, leading to accelerated renal disease. The pathology observed in this model is determined by the effector cell activation threshold that is established by the coexpression on infiltrating macrophages of the IgG2a/2b restricted activation receptor Fc gamma RIV and its inhibitory receptor counterpart, Fc gamma RIIB. Blocking Fc gamma RIV with a specific monoclonal antibody thereby preventing IgG2b engagement or treatment with high dose intravenous gamma-globulin (IVIG) to down-regulate Fc gamma RIV while up-regulating Fc gamma RIIB, protects mice from fatal disease. In the absence of Fc gamma RIIB, IVIG is not protective; this indicates that reduced Fc gamma RIV expression alone is insufficient to protect animals from pathogenic IgG2b immune complexes. These results establish the significance of specific IgG subclasses and their cognate FcR gamma s in renal disease.