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IgG3 deficiency extends lifespan and attenuates progression of glomerulonephritis in MRL/lpr mice
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 (-/-...
Autores principales: | , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
BioMed Central
2012
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3293080/ https://www.ncbi.nlm.nih.gov/pubmed/22248284 http://dx.doi.org/10.1186/1745-6150-7-3 |
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author | 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 |
author_facet | 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 |
author_sort | Greenspan, Neil S |
collection | PubMed |
description | 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. |
format | Online Article Text |
id | pubmed-3293080 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2012 |
publisher | BioMed Central |
record_format | MEDLINE/PubMed |
spelling | pubmed-32930802012-03-05 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 Biol Direct Research 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. BioMed Central 2012-01-16 /pmc/articles/PMC3293080/ /pubmed/22248284 http://dx.doi.org/10.1186/1745-6150-7-3 Text en Copyright ©2012 Greenspan et al; licensee BioMed Central Ltd. http://creativecommons.org/licenses/by/2.0 This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. |
spellingShingle | Research 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 |
title | IgG3 deficiency extends lifespan and attenuates progression of glomerulonephritis in MRL/lpr mice |
title_full | IgG3 deficiency extends lifespan and attenuates progression of glomerulonephritis in MRL/lpr mice |
title_fullStr | IgG3 deficiency extends lifespan and attenuates progression of glomerulonephritis in MRL/lpr mice |
title_full_unstemmed | IgG3 deficiency extends lifespan and attenuates progression of glomerulonephritis in MRL/lpr mice |
title_short | IgG3 deficiency extends lifespan and attenuates progression of glomerulonephritis in MRL/lpr mice |
title_sort | igg3 deficiency extends lifespan and attenuates progression of glomerulonephritis in mrl/lpr mice |
topic | Research |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3293080/ https://www.ncbi.nlm.nih.gov/pubmed/22248284 http://dx.doi.org/10.1186/1745-6150-7-3 |
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