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(American Journal of Pathology. 2003;162:1677-1683.)
© 2003 American Society for Investigative Pathology

Both Fc Receptor I and Fc Receptor III Mediate Disease in Accelerated Nephrotoxic Nephritis

Ruth M. Tarzi^*, Kevin A Davies^*, Jill W. C. Claassens, J. Sjef Verbeek, Mark J. Walport^* and H. Terence Cook

From the Division of Medicine^* and the Department of Histopathology, Hammersmith Hospital, Imperial College School of Medicine, London, United Kingdom; and the Department of Human and Clinical Genetics, Leiden University Medical Center, Leiden, The Netherlands

Recognition of immune complexes in glomeruli by activator Fc receptors (FcRI and FcRIII) is an important step in the development of glomerulonephritis. The low-affinity receptor (FcRIII) has previously been shown to be important in passive heterologous immune complex glomerulonephritis. However, most forms of human glomerulonephritis involve an active immune response, and the relative importance of FcRI (high-affinity receptor) and FcRIII in an active model of glomerulonephritis is not known. We have now studied accelerated nephrotoxic nephritis in FcRIII-/- mice and FcRI/III double-deficient mice, and compared them with matched wild-type controls and FcR chain-deficient (FcR-/-) mice. Mice were immunized against sheep IgG and injected with sheep anti-mouse glomerular basement membrane antibody 5 days later. Both FcRI/III double-deficient mice and FcR-/- mice were strongly protected from renal injury. In contrast, FcRIII-/- mice developed substantial nephritis, although there was a dose-dependent partial protection from glomerular crescents and thrombosis. Despite this histological protection from injury, the macrophage infiltrate was not reduced, implying a dissociation of macrophage accumulation from activation in the absence of activatory FcRIII. Therefore, both FcRI and FcRIII play a role in this active model of glomerulonephritis, because both had to be deficient to protect markedly from disease.

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