• An Erratum to this article was published on 23 September 2015

This article has been updated

Abstract

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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Change history

  • 21 January 2015

    Spelling of author S.K.S. was corrected.

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Acknowledgements

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.

Author information

Affiliations

  1. Division of Emergency Medicine, Cincinnati Children’s Hospital Medical Center, Cincinnati, Ohio 45229, USA

    • Richard T. Strait
    • , Ashley Mahler
    •  & Nathaniel Barasa
  2. Department of Pediatrics, University of Cincinnati College of Medicine, Cincinnati, Ohio 45267, USA

    • Richard T. Strait
  3. Department of Molecular Genetics, Biochemistry and Microbiology, University of Cincinnati College of Medicine, Cincinnati, Ohio 45267, USA

    • Monica T. Posgai
    •  & Andrew B. Herr
  4. Department of Medicine, University of Southern California School of Medicine, Los Angeles, California 90033, USA

    • Chaim O. Jacob
  5. Division of Immunobiology, Cincinnati Children’s Hospital Medical Center, Cincinnati, Ohio 45229, USA

    • Jörg Köhl
    • , Andrew B. Herr
    •  & Fred D. Finkelman
  6. Institute for Systemic Inflammation Research, University of Lübeck, 23538 Lübeck, Germany

    • Jörg Köhl
    •  & Marc Ehlers
  7. Division of Pathology, Cincinnati Children’s Hospital Medical Center, Cincinnati, Ohio 45229, USA

    • Keith Stringer
    • , Shiva Kumar Shanmukhappa
    •  & David Witte
  8. Division of Biostatistics and Epidemiology, Cincinnati Children’s Hospital Medical Center, Cincinnati, Ohio 45229, USA

    • Md Monir Hossain
  9. Division of Immunology, Allergy and Rheumatology, Department of Medicine, University of Cincinnati College of Medicine, Cincinnati, Ohio 45267, USA

    • Marat Khodoun
    •  & Fred D. Finkelman
  10. Medical Service, Cincinnati Veterans Affairs Medical Center, Cincinnati, Ohio 45220, USA

    • Fred D. Finkelman

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Contributions

R.T.S. planned, performed, interpreted and directed all experiments and participated in all drafts of the manuscript; M.K., A.M. and N.B. performed experiments; C.O.J. provided mice; J.K. provided mice and reagents and participated in planning of all complement-related studies; M.E. participated in the planning and interpretation of isotype switch variant studies; S.K.S., K.S. and D.W. performed and interpreted histological studies; M.T.P. and A.B.H. contributed to investigation of the importance of antibody hinge region length; M.M.H. performed statistical analyses; and F.D.F. designed the study, analysed data and wrote the initial draft of the paper. All authors discussed the results and commented on the manuscript.

Competing interests

The authors declare no competing financial interests.

Corresponding author

Correspondence to Fred D. Finkelman.

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DOI

https://doi.org/10.1038/nature13868

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