IgG1 protects against renal disease in a mouse model of cryoglobulinaemia
| Autor: | Andrew B. Herr, Monir Hossain, David P. Witte, Jörg Köhl, Shiva Kumar Shanmukhappa, Chaim O. Jacob, Marat Khodoun, Ashley Mahler, Marc Ehlers, Keith F. Stringer, Nathaniel Barasa, Monica T. Posgai, Richard T. Strait, Fred D. Finkelman |
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| Rok vydání: | 2011 |
| Předmět: |
Male
Antigen-Antibody Complex chemical and pharmacologic phenomena Binding Competitive Immunoglobulin G Article Classical complement pathway Mice Immune system Glomerulonephritis Immunopathology Animals Antigens Multidisciplinary biology Goats Receptors IgG Antibodies Monoclonal Complement System Proteins Isotype Immune complex Disease Models Animal Cryoglobulinemia Solubility Trinitrobenzenes Immunology biology.protein Female Antibody |
| Zdroj: | Nature |
| ISSN: | 1476-4687 |
| Popis: | Here, the predominant murine immunoglobulin G subclass, IgG1, which is a poor activator of effector mechanisms, is shown to have a regulatory function, protecting against the development of IgG3 immune-complex-driven renal disease by competing with IgG3 for antigen and increasing immune complex solubility. Some immunoglobulin isotypes, such as mouse IgG1 and human IgG4, have little ability to induce effector mechanisms: they don't efficiently activate complement, stimulate immunoglobulin crystallizable fragment receptors (FcRs), or aggregate antigens. So what do they do? Richard Strait et al. provide evidence IgG, the predominant murine IgG subclass has regulatory function and protects against the development of IgG3 immune complex driven renal disease by competing with IgG3 for antigen and increasing immune complex solubility. This result suggests that IgG isotypes that poorly activate effector mechanisms may inhibit immune complex immunopathology by other means. 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. |
| Databáze: | OpenAIRE |
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