title: IgG1 protects against renal disease in a mouse model of cryoglobulinaemia.
abstract: 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.
authors.affiliation: 1] Division of Emergency Medicine, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio 45229, USA [2] Department of Pediatrics, University of Cincinnati College of Medicine, Cincinnati, Ohio 45267, USA.
authors.forename: Richard T
authors.initials: RT
authors.lastname: Strait
authors.affiliation: Department of Molecular Genetics, Biochemistry and Microbiology, University of Cincinnati College of Medicine, Cincinnati, Ohio 45267, USA.
authors.forename: Monica T
authors.initials: MT
authors.lastname: Posgai
authors.affiliation: Division of Emergency Medicine, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio 45229, USA.
authors.forename: Ashley
authors.initials: A
authors.lastname: Mahler
authors.affiliation: Division of Emergency Medicine, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio 45229, USA.
authors.forename: Nathaniel
authors.initials: N
authors.lastname: Barasa
authors.affiliation: Department of Medicine, University of Southern California School of Medicine, Los Angeles, California 90033, USA.
authors.forename: Chaim O
authors.initials: CO
authors.lastname: Jacob
authors.affiliation: 1] Division of Immunobiology, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio 45229, USA [2] Institute for Systemic Inflammation Research, University of Lübeck, 23538 Lübeck, Germany.
authors.forename: Jörg
authors.initials: J
authors.lastname: Köhl
authors.affiliation: Institute for Systemic Inflammation Research, University of Lübeck, 23538 Lübeck, Germany.
authors.forename: Marc
authors.initials: M
authors.lastname: Ehlers
authors.affiliation: Division of Pathology, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio 45229, USA.
authors.forename: Keith
authors.initials: K
authors.lastname: Stringer
authors.affiliation: Division of Pathology, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio 45229, USA.
authors.forename: Shiva Kumar
authors.initials: SK
authors.lastname: Shanmukhappa
authors.affiliation: Division of Pathology, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio 45229, USA.
authors.forename: David
authors.initials: D
authors.lastname: Witte
authors.affiliation: Division of Biostatistics and Epidemiology, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio 45229, USA.
authors.forename: Md Monir
authors.initials: MM
authors.lastname: Hossain
authors.affiliation: Division of Immunology, Allergy and Rheumatology, Department of Medicine, University of Cincinnati College of Medicine, Cincinnati, Ohio 45267, USA.
authors.forename: Marat
authors.initials: M
authors.lastname: Khodoun
authors.affiliation: 1] Department of Molecular Genetics, Biochemistry and Microbiology, University of Cincinnati College of Medicine, Cincinnati, Ohio 45267, USA [2] Division of Immunobiology, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio 45229, USA.
authors.forename: Andrew B
authors.initials: AB
authors.lastname: Herr
authors.affiliation: 1] Division of Immunobiology, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio 45229, USA [2] Division of Immunology, Allergy and Rheumatology, Department of Medicine, University of Cincinnati College of Medicine, Cincinnati, Ohio 45267, USA [3] Medical Service, Cincinnati Veterans Affairs Medical Center, Cincinnati, Ohio 45220, USA.
authors.forename: Fred D
authors.initials: FD
authors.lastname: Finkelman
mesh_terms: D000818:Animals; D000911:Antibodies, Monoclonal / Q000276:immunology; D000936:Antigen-Antibody Complex / Q000737:chemistry / Q000276:immunology; D000941:Antigens / Q000276:immunology; D001667:Binding, Competitive; D003165:Complement System Proteins; D003449:Cryoglobulinemia / Q000150:complications* / Q000276:immunology / Q000473:pathology; D004195:Disease Models, Animal; D005260:Female; D005921:Glomerulonephritis / Q000209:etiology* / Q000276:immunology / Q000473:pathology / Q000517:prevention & control*; D006041:Goats; D007074:Immunoglobulin G / Q000276:immunology*; D008297:Male; D051379:Mice; D017452:Receptors, IgG; D012995:Solubility; D014301:Trinitrobenzenes / Q000276:immunology
chemical_list: D000911:Antibodies, Monoclonal; D000936:Antigen-Antibody Complex; D000941:Antigens; D007074:Immunoglobulin G; D017452:Receptors, IgG; D014301:Trinitrobenzenes; D003165:Complement System Proteins