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IgG1 protects against renal disease in a mouse model of cryoglobulinaemia.

Strait RT, Posgai MT, Mahler A, Barasa N, Jacob CO, Köhl J, Ehlers M, Stringer K, Shanmukhappa SK, Witte D, Hossain MM, Khodoun M, Herr AB, Finkelman FD - Nature (2014)

Bottom Line: 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).

View Article: PubMed Central - PubMed

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.

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.

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IgG1 inhibits IgG3-induced cryoglobulin kidney disease independent of complement and FcγRIIB and better than IgG2a and IgG2ba, WT mice (4/gp) were injected i.v. with 4 mg of mouse IgG1, IgG2a, IgG2b, or IgG3 anti-TNP mAb and s.c. with 100 μl of TNP-goat serum on days 0 and 1. Urine LE and blood measured prior to injections and on d1 and d2. b, Urine LE and blood for BALB/c WT and C3- mice (4/gp) injected i.v. with 4 mg of IgG3 anti-TNP mAb and s.c. with 400 μl of TNP-goat serum on d0 and 1. c, WT and FcγRIIB-deficient (FcγRIIB-) mice (4/gp) were injected s.c. with 100 μl of TNP-goat serum and i.v. with 4 mg of IgG3 anti-TNP ± 5 mg of IgG1 anti-TNP on d0 and 1. Urinalysis on d0, 1 and 2. d, BALB/c mice were injected i.v. with 4 mg of IgG3 anti-TNP and s.c. with 1.4 mg of TNP-BSA on days 0 and 1. Some mice were also injected with 0.625, 1.25, 2.5, or 5 mg of switch variants of IgG1, IgG2a or IgG2b anti-TNP mAbs on d0 and 1. Urine protein was determined on d0 (not shown), d1 (upper panel) and d2 (lower panel). Results are pooled from a total of 7 experiments. Group size: IgG3 alone: 19 mice; 0.625 mg of IgG1, IgG2a, or IgG2b: 4 mice; 1.25 mg of IgG1, IgG2a or IgG2b: 8 mice; 2.5 mg of IgG1, IgG2a or IgG2b: 6 mice; 5 mg of IgG1, IgG2a or IgG2b: 8 or 9 mice. The significance of differences between treatment groups was determined as described in the legend to Fig. 4f. # p<0.05 as compared to IgG2a plus IgG3. +p<0.05 as compared to IgG2b plus IgG3. *p<0.05 as compared to IgG3 alone. e, Binding of the Ig isotype switch variants to ELISA wells coated with TNP-BSA, reported as percentage of maximal binding. f, Binding of the Ig isotype switch variants to ELISA wells coated with IgG3 anti-TNP mAb. g, Binding of IgG3 and the Ig isotype switch variants to ELISA wells coated with themselves.
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Figure 7: IgG1 inhibits IgG3-induced cryoglobulin kidney disease independent of complement and FcγRIIB and better than IgG2a and IgG2ba, WT mice (4/gp) were injected i.v. with 4 mg of mouse IgG1, IgG2a, IgG2b, or IgG3 anti-TNP mAb and s.c. with 100 μl of TNP-goat serum on days 0 and 1. Urine LE and blood measured prior to injections and on d1 and d2. b, Urine LE and blood for BALB/c WT and C3- mice (4/gp) injected i.v. with 4 mg of IgG3 anti-TNP mAb and s.c. with 400 μl of TNP-goat serum on d0 and 1. c, WT and FcγRIIB-deficient (FcγRIIB-) mice (4/gp) were injected s.c. with 100 μl of TNP-goat serum and i.v. with 4 mg of IgG3 anti-TNP ± 5 mg of IgG1 anti-TNP on d0 and 1. Urinalysis on d0, 1 and 2. d, BALB/c mice were injected i.v. with 4 mg of IgG3 anti-TNP and s.c. with 1.4 mg of TNP-BSA on days 0 and 1. Some mice were also injected with 0.625, 1.25, 2.5, or 5 mg of switch variants of IgG1, IgG2a or IgG2b anti-TNP mAbs on d0 and 1. Urine protein was determined on d0 (not shown), d1 (upper panel) and d2 (lower panel). Results are pooled from a total of 7 experiments. Group size: IgG3 alone: 19 mice; 0.625 mg of IgG1, IgG2a, or IgG2b: 4 mice; 1.25 mg of IgG1, IgG2a or IgG2b: 8 mice; 2.5 mg of IgG1, IgG2a or IgG2b: 6 mice; 5 mg of IgG1, IgG2a or IgG2b: 8 or 9 mice. The significance of differences between treatment groups was determined as described in the legend to Fig. 4f. # p<0.05 as compared to IgG2a plus IgG3. +p<0.05 as compared to IgG2b plus IgG3. *p<0.05 as compared to IgG3 alone. e, Binding of the Ig isotype switch variants to ELISA wells coated with TNP-BSA, reported as percentage of maximal binding. f, Binding of the Ig isotype switch variants to ELISA wells coated with IgG3 anti-TNP mAb. g, Binding of IgG3 and the Ig isotype switch variants to ELISA wells coated with themselves.

Mentions: A passive immunization model was used to further test the hypothesis that renal disease can be caused by IgG3/Ag IC precipitation in glomerular capillaries. WT BALB/c mice were injected simultaneously with IgG3 anti-TNP mAb i.v.and TNP-goat serum (TNP-GIgG) s.c.on days 0 and 1. These mice developed increased BUN, urine protein, LE, and blood, and large deposits of amorphous material in glomerular capillaries on day 2 (Fig. 3a-c and Extended Data Fig. 7a). Similar lesions developed in similarly treated C3-deficient mice, (Fig. 3d and Extended Data Fig. 7b) and FcRγ-deficient mice, as well as in C57BL/6 mice and in BALB/c WT mice when TNP-BSA was substituted for TNP-GIgG (not shown). WT mice injected with TNP-GIgG plus IgG1, IgG2a, or IgG2b anti-TNP mAb failed to develop renal disease (Fig. 3a and Extended Data Fig. 7a). None of the mAbs induced disease when injected without TNP (Fig. 3b and data not shown).


IgG1 protects against renal disease in a mouse model of cryoglobulinaemia.

Strait RT, Posgai MT, Mahler A, Barasa N, Jacob CO, Köhl J, Ehlers M, Stringer K, Shanmukhappa SK, Witte D, Hossain MM, Khodoun M, Herr AB, Finkelman FD - Nature (2014)

IgG1 inhibits IgG3-induced cryoglobulin kidney disease independent of complement and FcγRIIB and better than IgG2a and IgG2ba, WT mice (4/gp) were injected i.v. with 4 mg of mouse IgG1, IgG2a, IgG2b, or IgG3 anti-TNP mAb and s.c. with 100 μl of TNP-goat serum on days 0 and 1. Urine LE and blood measured prior to injections and on d1 and d2. b, Urine LE and blood for BALB/c WT and C3- mice (4/gp) injected i.v. with 4 mg of IgG3 anti-TNP mAb and s.c. with 400 μl of TNP-goat serum on d0 and 1. c, WT and FcγRIIB-deficient (FcγRIIB-) mice (4/gp) were injected s.c. with 100 μl of TNP-goat serum and i.v. with 4 mg of IgG3 anti-TNP ± 5 mg of IgG1 anti-TNP on d0 and 1. Urinalysis on d0, 1 and 2. d, BALB/c mice were injected i.v. with 4 mg of IgG3 anti-TNP and s.c. with 1.4 mg of TNP-BSA on days 0 and 1. Some mice were also injected with 0.625, 1.25, 2.5, or 5 mg of switch variants of IgG1, IgG2a or IgG2b anti-TNP mAbs on d0 and 1. Urine protein was determined on d0 (not shown), d1 (upper panel) and d2 (lower panel). Results are pooled from a total of 7 experiments. Group size: IgG3 alone: 19 mice; 0.625 mg of IgG1, IgG2a, or IgG2b: 4 mice; 1.25 mg of IgG1, IgG2a or IgG2b: 8 mice; 2.5 mg of IgG1, IgG2a or IgG2b: 6 mice; 5 mg of IgG1, IgG2a or IgG2b: 8 or 9 mice. The significance of differences between treatment groups was determined as described in the legend to Fig. 4f. # p<0.05 as compared to IgG2a plus IgG3. +p<0.05 as compared to IgG2b plus IgG3. *p<0.05 as compared to IgG3 alone. e, Binding of the Ig isotype switch variants to ELISA wells coated with TNP-BSA, reported as percentage of maximal binding. f, Binding of the Ig isotype switch variants to ELISA wells coated with IgG3 anti-TNP mAb. g, Binding of IgG3 and the Ig isotype switch variants to ELISA wells coated with themselves.
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Figure 7: IgG1 inhibits IgG3-induced cryoglobulin kidney disease independent of complement and FcγRIIB and better than IgG2a and IgG2ba, WT mice (4/gp) were injected i.v. with 4 mg of mouse IgG1, IgG2a, IgG2b, or IgG3 anti-TNP mAb and s.c. with 100 μl of TNP-goat serum on days 0 and 1. Urine LE and blood measured prior to injections and on d1 and d2. b, Urine LE and blood for BALB/c WT and C3- mice (4/gp) injected i.v. with 4 mg of IgG3 anti-TNP mAb and s.c. with 400 μl of TNP-goat serum on d0 and 1. c, WT and FcγRIIB-deficient (FcγRIIB-) mice (4/gp) were injected s.c. with 100 μl of TNP-goat serum and i.v. with 4 mg of IgG3 anti-TNP ± 5 mg of IgG1 anti-TNP on d0 and 1. Urinalysis on d0, 1 and 2. d, BALB/c mice were injected i.v. with 4 mg of IgG3 anti-TNP and s.c. with 1.4 mg of TNP-BSA on days 0 and 1. Some mice were also injected with 0.625, 1.25, 2.5, or 5 mg of switch variants of IgG1, IgG2a or IgG2b anti-TNP mAbs on d0 and 1. Urine protein was determined on d0 (not shown), d1 (upper panel) and d2 (lower panel). Results are pooled from a total of 7 experiments. Group size: IgG3 alone: 19 mice; 0.625 mg of IgG1, IgG2a, or IgG2b: 4 mice; 1.25 mg of IgG1, IgG2a or IgG2b: 8 mice; 2.5 mg of IgG1, IgG2a or IgG2b: 6 mice; 5 mg of IgG1, IgG2a or IgG2b: 8 or 9 mice. The significance of differences between treatment groups was determined as described in the legend to Fig. 4f. # p<0.05 as compared to IgG2a plus IgG3. +p<0.05 as compared to IgG2b plus IgG3. *p<0.05 as compared to IgG3 alone. e, Binding of the Ig isotype switch variants to ELISA wells coated with TNP-BSA, reported as percentage of maximal binding. f, Binding of the Ig isotype switch variants to ELISA wells coated with IgG3 anti-TNP mAb. g, Binding of IgG3 and the Ig isotype switch variants to ELISA wells coated with themselves.
Mentions: A passive immunization model was used to further test the hypothesis that renal disease can be caused by IgG3/Ag IC precipitation in glomerular capillaries. WT BALB/c mice were injected simultaneously with IgG3 anti-TNP mAb i.v.and TNP-goat serum (TNP-GIgG) s.c.on days 0 and 1. These mice developed increased BUN, urine protein, LE, and blood, and large deposits of amorphous material in glomerular capillaries on day 2 (Fig. 3a-c and Extended Data Fig. 7a). Similar lesions developed in similarly treated C3-deficient mice, (Fig. 3d and Extended Data Fig. 7b) and FcRγ-deficient mice, as well as in C57BL/6 mice and in BALB/c WT mice when TNP-BSA was substituted for TNP-GIgG (not shown). WT mice injected with TNP-GIgG plus IgG1, IgG2a, or IgG2b anti-TNP mAb failed to develop renal disease (Fig. 3a and Extended Data Fig. 7a). None of the mAbs induced disease when injected without TNP (Fig. 3b and data not shown).

Bottom Line: 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).

View Article: PubMed Central - PubMed

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.

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.

Show MeSH
Related in: MedlinePlus