Augmentation of NZB autoimmune phenotypes by the Sle1c murine lupus susceptibility interval.
The Sle1c lupus susceptibility interval spans a 7-Mb region on distal murine chromosome 1. Cr2 is the strongest candidate gene for lupus susceptibility in this interval, as its protein products are structurally and functionally altered. B6.Sle1c congenic mice develop Abs to chromatin by 9 mo of age with a 30% penetrance and do not develop GN. To determine whether the New Zealand White (NZW)-derived Sle1c interval would interact with New Zealand Black (NZB) genes to result in enhanced autoimmune phenotypes, NZB mice were bred with B6 or B6.Sle1c congenic mice and approximately 20 female offspring were selected from each breeding for longitudinal study. These mice differ only at the Sle1c locus at which they have either a NZB/B6 or NZB/NZW genotype. NZB x B6.Sle1c mice had an accelerated onset of anti-chromatin Abs (100 vs 68% at 6 mo, p = 0.006) and anti-dsDNA Abs (45 vs 5% at 9 mo, p = 0.0048). Furthermore, median titers of anti-chromatin and anti-dsDNA Abs were significantly higher in the NZB x B6.Sle1c group compared with the NZB x B6 group. This corresponded with a higher prevalence of proliferative GN at 12 mo (55 vs 16%, p = 0.0214) as well as increased glomerular deposition of C3 (p = 0.0272) and IgG (p = 0.032), although blood urea nitrogen remained normal and significant proteinuria was not identified in either group. These data show that the Sle1c interval accelerates and augments the loss of tolerance to chromatin and dsDNA induced by NZB genes and induces significantly greater end-organ damage.
Giles
Brendan M
BM
Department of Medicine and Department of Immunology, University of Colorado at Denver and Health Sciences Center, Aurora, CO 80045, USA.
Tchepeleva
Svetlana N
SN
Kachinski
Julie J
JJ
Ruff
Katherine
K
Croker
Byron P
BP
Morel
Laurence
L
Boackle
Susan A
SA
D000818:Animals; D000974:Antibodies, Antinuclear / Q000097:blood* / Q000235:genetics / Q000276:immunology; D001327:Autoimmune Diseases / Q000235:genetics* / Q000276:immunology; D001947:Breeding; D002843:Chromatin / Q000276:immunology*; D002875:Chromosomes / Q000235:genetics; D004247:DNA / Q000276:immunology*; D020022:Genetic Predisposition to Disease; D007108:Immune Tolerance / Q000235:genetics; D007136:Immunoglobulins / Q000032:analysis; D007678:Kidney Glomerulus / Q000737:chemistry / Q000276:immunology; D008180:Lupus Erythematosus, Systemic / Q000235:genetics* / Q000276:immunology; D051379:Mice; D008814:Mice, Inbred NZB; D008817:Mice, Mutant Strains; D010641:Phenotype; D017463:Receptors, Complement 3b / Q000276:immunology; D017464:Receptors, Complement 3d / Q000235:genetics / Q000276:immunology; D051437:Renal Insufficiency / Q000235:genetics
D000974:Antibodies, Antinuclear; D002843:Chromatin; D007136:Immunoglobulins; D017463:Receptors, Complement 3b; D017464:Receptors, Complement 3d; D004247:DNA