title: IgG3 deficiency extends lifespan and attenuates progression of glomerulonephritis in MRL/lpr mice.
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.
authors.affiliation: Department of Pathology, Case Western Reserve University School of Medicine, Cleveland, Ohio 44106-4943, USA. neil.greenspan@case.edu
authors.forename: Neil S
authors.initials: NS
authors.lastname: Greenspan
authors.forename: Myro A
authors.initials: MA
authors.lastname: Lu
authors.forename: Jacob W
authors.initials: JW
authors.lastname: Shipley
authors.forename: Xuedong
authors.initials: X
authors.lastname: Ding
authors.forename: Qing
authors.initials: Q
authors.lastname: Li
authors.forename: Dilara
authors.initials: D
authors.lastname: Sultana
authors.forename: Maria
authors.initials: M
authors.lastname: Kollaros
authors.forename: John R
authors.initials: JR
authors.lastname: Schreiber
authors.forename: Pingfu
authors.initials: P
authors.lastname: Fu
authors.forename: Chaim
authors.initials: C
authors.lastname: Putterman
authors.forename: Steven N
authors.initials: SN
authors.lastname: Emancipator
mesh_terms: D000185:Actinin / Q000235:genetics / Q000276:immunology; D000367:Age Factors; D000483:Alleles; D000818:Animals; D001323:Autoantibodies / Q000097:blood / Q000276:immunology; D003404:Creatinine / Q000097:blood / Q000652:urine; D004247:DNA / Q000235:genetics / Q000276:immunology; D018450:Disease Progression; D005260:Female; D005838:Genotype; D005921:Glomerulonephritis / Q000097:blood / Q000235:genetics / Q000276:immunology / Q000473:pathology*; D007074:Immunoglobulin G / Q000032:analysis / Q000097:blood / Q000276:immunology*; D007153:Immunologic Deficiency Syndromes / Q000276:immunology / Q000473:pathology; D007178:Inbreeding; D007668:Kidney / Q000166:cytology / Q000276:immunology / Q000473:pathology; D008136:Longevity; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D019463:Mice, Inbred MRL lpr; D020641:Polymorphism, Single Nucleotide; D016019:Survival Analysis
chemical_list: D001323:Autoantibodies; D007074:Immunoglobulin G; D000185:Actinin; D004247:DNA; D003404:Creatinine