Immunoglobulins protect against disease to a considerable extent by activating complement and stimulatory immunoglobulin crystallizable fragment receptors (Ig FcRs), and aggregating microbial pathogens1,2. Yet IgG1, the predominant murine serum Ig isotype, cannot activate complement by the classical pathway, binds more avidly to an inhibitory than to stimulatory FcRs, and has limited ability to aggregate pathogens1,2,3. In these regards, it resembles human IgG4 (ref. 4). We hypothesized that limited ability to activate effector mechanisms might protect against immune complex immunopathology. Here we show that IgG1-deficient (γ1−) mice5, immunized with a potent antigen, develop lethal renal disease soon after they begin to produce antigen-specific antibody, whereas similarly immunized wild-type mice remain healthy. Surprisingly, renal disease in this model is complement and FcR independent and results from immune complex precipitation in glomerular capillaries, as in some cryoglobulinaemic humans6. IgG3, which self-associates to form large immune complexes7,8, accounts for more than 97% of the mouse Ig in this cryoglobulin; furthermore, glomerular disease develops when mice are injected with IgG3 anti-trinitrophenyl (TNP) monoclonal antibody followed by a TNP-labelled protein. Renal disease is prevented in both active and passive immunization models by antigen-specific IgG1; other isotypes are less potent at preventing disease. These observations demonstrate the adaptive significance of Ig isotypes that poorly activate effector mechanisms, reveal an immune-complex-dependent, complement- and FcR-independent nephrotoxic mechanism, and suggest that isotypes that poorly activate effector mechanisms may be useful for inhibiting immune complex immunopathology.
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We thank M. Wills-Karp for C3-deficient mice, D. Metzger for J-chain-deficient mice, M. Muramatsu for AID-deficient mice, S. Izui for a hybridoma that secretes mouse IgG1 anti-TNP monoclonal antibody, M. Robson and L. Aarden for switch variant hybridomas that secrete mouse IgG1, IgG2a and IgG2b anti-TNP monoclonal antibodies, B. DiPasquale for histological staining, and J. Lambris for C5aR antagonist. Research was supported by a US Department of Veterans Affairs Merit Award, National Institutes of Health R01 AI072040, and the University of Cincinnati and Cincinnati Children’s Hospital, all to F.D.F.