IgG3 deficiency extends lifespan and attenuates progression of glomerulonephritis in MRL/lpr mice

Neil S. Greenspan, Myro A. Lu, Jacob W. Shipley, Xuedong Ding, Qing Li, Dilara Sultana, Maria Kollaros, John R. Schreiber, Pingfu Fu, Chaim Putterman, Steven N. Emancipator

Research output: Contribution to journalArticle

22 Citations (Scopus)

Abstract

Background: Antibodies of the IgG3 subclass have been implicated in the pathogenesis of the spontaneous glomerulonephritis observed in mice of the MRL/MpJ-Tnfrsf6lpr (MRL/lpr) inbred strain which have been widely studied as a model of systemic lupus erythematosus We have produced IgG3-deficient (-/-) mice with the MRL/lpr genetic background to determine whether IgG3 antibodies are necessary for or at least contributory to MRL/lpr-associated nephritis.Results: The gamma3 genotype (+/+ vs. +/- vs. -/-) did not appear to significantly affect serum titers of IgG auto-antibodies specific for double-stranded DNA (dsDNA) or α-actinin. However, while substantial serum titers of IgG3 auto-antibodies specific for double-stranded DNA (dsDNA) or α-actinin were seen in gamma3 +/+ mice, somewhat lower serum titers of these IgG3 auto-antibodies were found in gamma3 +/- mice, and gamma3 -/- mice exhibited baseline concentrations of these auto-antibodies. Analysis of immunoglobulins eluted from snap-frozen kidneys obtained from mice of all three gamma3 genotypes at ~18 weeks of age revealed much higher quantities of IgG in the kidneys from gamma3 +/+ than gamma3 -/- mice, and most IgG eluted from +/+ mice was IgG3. The serum creatinine levels in gamma3 +/+ mice substantially exceeded those of age-matched gamma3 -/- mice after ~21 weeks of age. Histopathological examination of kidneys from mice sacrificed at pre-determined ages also revealed more extensive glomerulosclerosis in gamma3 +/+ or +/- mice than in -/- mice beginning at 21 weeks of age. Survival analysis for IgG3-deficient and IgG3-producing MRL/lpr mice revealed that gamma3 -/- mice lived significantly longer (p = 0.0006) than either gamma3 +/- or +/+ mice. Spontaneous death appeared to be due to irreversible renal failure, because > 85% of glomeruli in kidneys from mice that died spontaneously were obliterated by glomerulosclerosis.Conclusions: The available evidence suggests that IgG3 deficiency partially protects MRL/lpr mice against glomerulonephritis-associated morbidity and mortality by slowing or arresting the progression to glomerulosclerosis.Reviewers: This article was reviewed by Pushpa Pandiyan, Irun Cohen, and Etienne Joly.

Original languageEnglish (US)
Article number3
JournalBiology Direct
Volume7
DOIs
StatePublished - Jan 16 2012

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glomerulonephritis
Life Span
Glomerulonephritis
Progression
Antibodies
antibody
Mouse
Immunoglobulin G
serum
mice
Autoantibodies
autoantibodies
genotype
Kidney
Actinin
morbidity
kidneys
Genotype
Serum
Antibody

ASJC Scopus subject areas

  • Agricultural and Biological Sciences(all)
  • Biochemistry, Genetics and Molecular Biology(all)
  • Immunology
  • Applied Mathematics
  • Modeling and Simulation
  • Ecology, Evolution, Behavior and Systematics

Cite this

Greenspan, N. S., Lu, M. A., Shipley, J. W., Ding, X., Li, Q., Sultana, D., ... Emancipator, S. N. (2012). IgG3 deficiency extends lifespan and attenuates progression of glomerulonephritis in MRL/lpr mice. Biology Direct, 7, [3]. https://doi.org/10.1186/1745-6150-7-3

IgG3 deficiency extends lifespan and attenuates progression of glomerulonephritis in MRL/lpr mice. / Greenspan, Neil S.; Lu, Myro A.; Shipley, Jacob W.; Ding, Xuedong; Li, Qing; Sultana, Dilara; Kollaros, Maria; Schreiber, John R.; Fu, Pingfu; Putterman, Chaim; Emancipator, Steven N.

In: Biology Direct, Vol. 7, 3, 16.01.2012.

Research output: Contribution to journalArticle

Greenspan, NS, Lu, MA, Shipley, JW, Ding, X, Li, Q, Sultana, D, Kollaros, M, Schreiber, JR, Fu, P, Putterman, C & Emancipator, SN 2012, 'IgG3 deficiency extends lifespan and attenuates progression of glomerulonephritis in MRL/lpr mice', Biology Direct, vol. 7, 3. https://doi.org/10.1186/1745-6150-7-3
Greenspan, Neil S. ; Lu, Myro A. ; Shipley, Jacob W. ; Ding, Xuedong ; Li, Qing ; Sultana, Dilara ; Kollaros, Maria ; Schreiber, John R. ; Fu, Pingfu ; Putterman, Chaim ; Emancipator, Steven N. / IgG3 deficiency extends lifespan and attenuates progression of glomerulonephritis in MRL/lpr mice. In: Biology Direct. 2012 ; Vol. 7.
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abstract = "Background: Antibodies of the IgG3 subclass have been implicated in the pathogenesis of the spontaneous glomerulonephritis observed in mice of the MRL/MpJ-Tnfrsf6lpr (MRL/lpr) inbred strain which have been widely studied as a model of systemic lupus erythematosus We have produced IgG3-deficient (-/-) mice with the MRL/lpr genetic background to determine whether IgG3 antibodies are necessary for or at least contributory to MRL/lpr-associated nephritis.Results: The gamma3 genotype (+/+ vs. +/- vs. -/-) did not appear to significantly affect serum titers of IgG auto-antibodies specific for double-stranded DNA (dsDNA) or α-actinin. However, while substantial serum titers of IgG3 auto-antibodies specific for double-stranded DNA (dsDNA) or α-actinin were seen in gamma3 +/+ mice, somewhat lower serum titers of these IgG3 auto-antibodies were found in gamma3 +/- mice, and gamma3 -/- mice exhibited baseline concentrations of these auto-antibodies. Analysis of immunoglobulins eluted from snap-frozen kidneys obtained from mice of all three gamma3 genotypes at ~18 weeks of age revealed much higher quantities of IgG in the kidneys from gamma3 +/+ than gamma3 -/- mice, and most IgG eluted from +/+ mice was IgG3. The serum creatinine levels in gamma3 +/+ mice substantially exceeded those of age-matched gamma3 -/- mice after ~21 weeks of age. Histopathological examination of kidneys from mice sacrificed at pre-determined ages also revealed more extensive glomerulosclerosis in gamma3 +/+ or +/- mice than in -/- mice beginning at 21 weeks of age. Survival analysis for IgG3-deficient and IgG3-producing MRL/lpr mice revealed that gamma3 -/- mice lived significantly longer (p = 0.0006) than either gamma3 +/- or +/+ mice. Spontaneous death appeared to be due to irreversible renal failure, because > 85{\%} of glomeruli in kidneys from mice that died spontaneously were obliterated by glomerulosclerosis.Conclusions: The available evidence suggests that IgG3 deficiency partially protects MRL/lpr mice against glomerulonephritis-associated morbidity and mortality by slowing or arresting the progression to glomerulosclerosis.Reviewers: This article was reviewed by Pushpa Pandiyan, Irun Cohen, and Etienne Joly.",
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AU - Lu, Myro A.

AU - Shipley, Jacob W.

AU - Ding, Xuedong

AU - Li, Qing

AU - Sultana, Dilara

AU - Kollaros, Maria

AU - Schreiber, John R.

AU - Fu, Pingfu

AU - Putterman, Chaim

AU - Emancipator, Steven N.

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N2 - Background: Antibodies of the IgG3 subclass have been implicated in the pathogenesis of the spontaneous glomerulonephritis observed in mice of the MRL/MpJ-Tnfrsf6lpr (MRL/lpr) inbred strain which have been widely studied as a model of systemic lupus erythematosus We have produced IgG3-deficient (-/-) mice with the MRL/lpr genetic background to determine whether IgG3 antibodies are necessary for or at least contributory to MRL/lpr-associated nephritis.Results: The gamma3 genotype (+/+ vs. +/- vs. -/-) did not appear to significantly affect serum titers of IgG auto-antibodies specific for double-stranded DNA (dsDNA) or α-actinin. However, while substantial serum titers of IgG3 auto-antibodies specific for double-stranded DNA (dsDNA) or α-actinin were seen in gamma3 +/+ mice, somewhat lower serum titers of these IgG3 auto-antibodies were found in gamma3 +/- mice, and gamma3 -/- mice exhibited baseline concentrations of these auto-antibodies. Analysis of immunoglobulins eluted from snap-frozen kidneys obtained from mice of all three gamma3 genotypes at ~18 weeks of age revealed much higher quantities of IgG in the kidneys from gamma3 +/+ than gamma3 -/- mice, and most IgG eluted from +/+ mice was IgG3. The serum creatinine levels in gamma3 +/+ mice substantially exceeded those of age-matched gamma3 -/- mice after ~21 weeks of age. Histopathological examination of kidneys from mice sacrificed at pre-determined ages also revealed more extensive glomerulosclerosis in gamma3 +/+ or +/- mice than in -/- mice beginning at 21 weeks of age. Survival analysis for IgG3-deficient and IgG3-producing MRL/lpr mice revealed that gamma3 -/- mice lived significantly longer (p = 0.0006) than either gamma3 +/- or +/+ mice. Spontaneous death appeared to be due to irreversible renal failure, because > 85% of glomeruli in kidneys from mice that died spontaneously were obliterated by glomerulosclerosis.Conclusions: The available evidence suggests that IgG3 deficiency partially protects MRL/lpr mice against glomerulonephritis-associated morbidity and mortality by slowing or arresting the progression to glomerulosclerosis.Reviewers: This article was reviewed by Pushpa Pandiyan, Irun Cohen, and Etienne Joly.

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