IgG1 protects against renal disease in a mouse model of cryoglobulinaemia

Nature. 2015 Jan 22;517(7535):501-4. doi: 10.1038/nature13868. Epub 2014 Nov 2.


Immunoglobulins protect against disease to a considerable extent by activating complement and stimulatory immunoglobulin crystallizable fragment receptors (Ig FcRs), and aggregating microbial pathogens. 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 pathogens. 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(-)) mice, 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 humans. IgG3, which self-associates to form large immune complexes, 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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Animals
  • Antibodies, Monoclonal / immunology
  • Antigen-Antibody Complex / chemistry
  • Antigen-Antibody Complex / immunology
  • Antigens / immunology
  • Binding, Competitive
  • Complement System Proteins
  • Cryoglobulinemia / complications*
  • Cryoglobulinemia / immunology
  • Cryoglobulinemia / pathology
  • Disease Models, Animal
  • Female
  • Glomerulonephritis / etiology*
  • Glomerulonephritis / immunology
  • Glomerulonephritis / pathology
  • Glomerulonephritis / prevention & control*
  • Goats
  • Immunoglobulin G / immunology*
  • Male
  • Mice
  • Receptors, IgG
  • Solubility
  • Trinitrobenzenes / immunology


  • Antibodies, Monoclonal
  • Antigen-Antibody Complex
  • Antigens
  • Immunoglobulin G
  • Receptors, IgG
  • Trinitrobenzenes
  • Complement System Proteins