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 FcgammaRIV and its inhibitory receptor counterpart, FcgammaRIIB. Blocking FcgammaRIV with a specific monoclonal antibody thereby preventing IgG2b engagement or treatment with high dose intravenous gamma-globulin (IVIG) to down-regulate FcgammaRIV while up-regulating FcgammaRIIB, protects mice from fatal disease. In the absence of FcgammaRIIB, IVIG is not protective; this indicates that reduced FcgammaRIV expression alone is insufficient to protect animals from pathogenic IgG2b immune complexes. These results establish the significance of specific IgG subclasses and their cognate FcgammaRs in renal disease.
Kaneko
Yoshikatsu
Y
Laboratory of Molecular Genetics and Immunology, The Rockefeller University, New York, NY 10021, USA.
Nimmerjahn
Falk
F
Madaio
Michael P
MP
Ravetch
Jeffrey V
JV
D000818:Animals; D000911:Antibodies, Monoclonal / Q000008:administration & dosage / Q000276:immunology; D000936:Antigen-Antibody Complex / Q000276:immunology; D015536:Down-Regulation / Q000187:drug effects / Q000276:immunology; D050533:Glomerular Basement Membrane / Q000276:immunology / Q000473:pathology; D006801:Humans; D007105:Immune Complex Diseases / Q000188:drug therapy / Q000276:immunology* / Q000473:pathology*; D007074:Immunoglobulin G / Q000276:immunology*; D016756:Immunoglobulins, Intravenous / Q000008:administration & dosage / Q000276:immunology; D007155:Immunologic Factors / Q000008:administration & dosage / Q000276:immunology; D008264:Macrophages / Q000276:immunology / Q000473:pathology; D051379:Mice; D009393:Nephritis / Q000188:drug therapy / Q000276:immunology* / Q000473:pathology*; D011961:Receptors, Fc / Q000276:immunology*; D015854:Up-Regulation / Q000187:drug effects / Q000276:immunology
D000911:Antibodies, Monoclonal; D000936:Antigen-Antibody Complex; D007074:Immunoglobulin G; D016756:Immunoglobulins, Intravenous; D007155:Immunologic Factors; D011961:Receptors, Fc