IgG1 protects against renal disease in a mouse model of cryoglobulinaemia

摘要

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 cryoglobu-linaemic 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.%一些免疫球蛋白异形体(如小鼠IgG1和人类IgG4)几乎没有能力诱导效应子机制: 它们不能高效活化、补足、刺激免疫球蛋白可结晶片段受体(FcRs)或聚集抗原。那么它们干什么呢？ Richard Strait等人提供的证据表明，IgG1(占主导地位的小鼠IgG子类)有调控功能，通过与IgG3竞争抗原和提高免疫复合物可溶性来防止由IgG3免疫复合物驱动的肾病的发生。这一结果表明，在活化效应子机制方面性能差的IgG异形体也许能通过其他手段防止由免疫复合物造成的免疫疾病。