IgG3 deficiency extends lifespan and attenuates progression of glomerulonephritis in MRL/lpr mice. Biol Direct 2012 Jan 16;7:3
Date
01/18/2012Pubmed ID
22248284Pubmed Central ID
PMC3293080DOI
10.1186/1745-6150-7-3Scopus ID
2-s2.0-84855800449 (requires institutional sign-in at Scopus site) 27 CitationsAbstract
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.
Author List
Greenspan NS, Lu MA, Shipley JW, Ding X, Li Q, Sultana D, Kollaros M, Schreiber JR, Fu P, Putterman C, Emancipator SNMESH terms used to index this publication - Major topics in bold
ActininAge Factors
Alleles
Animals
Autoantibodies
Creatinine
DNA
Disease Progression
Female
Genotype
Glomerulonephritis
Immunoglobulin G
Immunologic Deficiency Syndromes
Inbreeding
Kidney
Longevity
Male
Mice
Mice, Inbred BALB C
Mice, Inbred C57BL
Mice, Inbred MRL lpr
Polymorphism, Single Nucleotide
Survival Analysis
