The Journal of Experimental Medicine
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Published online 6 March 2006 doi:10.1084/jem.20051900
Rockefeller University Press, 0022-1007 $8.00
JEM, Volume 203, Number 3, 789-797
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ARTICLE

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

Yoshikatsu Kaneko1, Falk Nimmerjahn1, Michael P. Madaio2, and Jeffrey V. Ravetch1

1 Laboratory of Molecular Genetics and Immunology, The Rockefeller University, New York, NY 10021
2 Renal Electrolyte and Hypertension Division, The University of Pennsylvania, Philadelphia, PA 19104

CORRESPONDENCE Jeffrey V. Ravetch: ravetch{at}rockefeller.edu

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 Fc{gamma}Rs in renal disease.

Abbreviations used: BUN, blood urea nitrogen; GBM, glomerular basement membrane; ITP, idiopathic thrombocytopenic purpura; IVIG, intravenous {gamma}-globulin; NTS, anti-GBM antiserum; PAS, periodic acid-Schiff.


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