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FcRIII and FcRIV Are Indispensable for Acute Glomerular Inflammation Induced by Switch Variant Monoclonal Antibodies¹

Angela Giorgini^*, Heather J. Brown^*, Helen R. Lock^*, Falk Nimmerjahn, Jeffrey V. Ravetch, J. Sjef Verbeek, Steven H. Sacks^* and Michael G. Robson^2,*

^* Medical Research Council Centre for Transplantation, Kings College London School of Medicine, Guy’s Hospital, London, U.K.; Laboratory of Experimental Immunology and Immunotherapy, Nikolaus-Fiebiger-Center for Molecular Medicine, University of Erlangen-Nuremberg, Erlangen, Germany; Laboratory of Molecular Genetics and Immunology, Rockefeller University, New York, NY 10021; and Department of Human Genetics, Leiden University Medical Center, Leiden, The Netherlands

The relative ability of IgG subclasses to cause acute inflammation and the roles of specific effector mechanisms in this process are not clear. We explored this in an in vivo model of glomerular inflammation in the mouse. Trinitrophenol was planted on the glomerular basement membrane after conjugation to nephrotoxic Ab. The relative nephritogenicity of anti-trinitrophenol switch variant mAbs was then explored and shown to be IgG2a > IgG2b, with no disease caused by IgG1. Using knockout mice, we showed that FcRIII was necessary for both neutrophil influx and glomerular damage induced by IgG2a and IgG2b. Surprisingly, IgG1 did not cause disease although it binds to FcRIII. Using blocking Abs, we showed that this was explained by an additional requirement for FcRIV, which does not bind to IgG1. IgG2a- or IgG2b-induced neutrophil influx was not affected by deficiency of either FcRI or C3. Bone marrow chimeras were constructed to test the effect of combined deficiency of FcRI and C3, and there was no effect on IgG2a- or IgG2b-mediated neutrophil influx. However, IgG2b-induced albuminuria and thrombosis were reduced in C3-deficient mice, showing an additional role for complement in IgG2b-mediated glomerular damage. The results show that IgG2a and IgG2b are the pathogenic subclasses in acute neutrophil-mediated glomerular inflammation, with an indispensable role for both FcRIII and FcRIV. Additionally, complement contributes to IgG2b-induced glomerular injury.

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ This work was funded by the Wellcome Trust.

² Address correspondence and reprint requests to Dr. Michael Robson, Medical Research Council Centre for Transplantation, King’s College London School of Medicine, Guy’s Hospital, London SE1 9RT, U.K. E-mail address: michael.robson{at}kcl.ac.uk

³ Abbreviations used in this paper: GN, glomerulonephritis; TNP, trinitrophenol.

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