title: Contribution of major histocompatibility complex (MHC) to upregulation of anti-DNA antibody in transgenic mice.
abstract: Genes linked to the MHC class II contribute to human and murine lupus, but multiple genes are required to produce and upregulate pathogenic autoantibodies. In NZB/NZW mice, nephritogenic IgG anti-dsDNA is provided by NZW (H-2z), but the origin of the upregulating signals is unknown. They could be from NZB (H-2d) or NZW (H-2z) or require heterozygocity. Our aim was to determine whether NZW can provide upregulating signals for the nephritogenic autoantibody introduced to normal mice via transgenes encoding a NZB/NZW IgG2a antibody to DNA. These transgenic mice spontaneously secrete serum IgG2a anti-DNA, some develop clinical nephritis with proteinuria and azotemia, but none die of fatal nephritis. We bred mice to produce offspring of H-2b/d, H-2b/b, H-2b/z and H-2d/z haplotypes (H-2b, H-2d and H-2z derived from C57BL/6, BALB/c and NZW, respectively). Transgenic H-2b/d mice had significantly higher levels of serum anti-DNA antibodies compared with H-2b/b haplotypes from 20 to 40 weeks of age (P < 0.05). However, unlike NZB/NZW mice, they did not show sustained upregulation of anti-DNA antibodies. The serum levels of IgG anti-DNA of transgenic mice declined after 30 weeks of age. In order to determine whether NZW can provide upregulating signals, we introduced the NZW background into transgenic H-2b/d mice in an attempt to increase both quantities of anti-DNA and prevalence of nephritis. However, serum levels of anti-DNA antibodies were similar in transgenic mice of H-2b/z and H-2d/z haplotypes. The anti-DNA levels declined with age in both groups. No mice developed fatal nephritis.(ABSTRACT TRUNCATED AT 250 WORDS)
authors.affiliation: Department of Medicine, University of California, Los Angeles 90024.
authors.forename: Y W
authors.initials: YW
authors.lastname: Song
authors.forename: B P
authors.initials: BP
authors.lastname: Tsao
authors.forename: B H
authors.initials: BH
authors.lastname: Hahn
mesh_terms: D000818:Animals; D000974:Antibodies, Antinuclear / Q000096:biosynthesis*; D001327:Autoimmune Diseases / Q000235:genetics / Q000276:immunology*; D003433:Crosses, Genetic; D004195:Disease Models, Animal; D005260:Female; D005786:Gene Expression Regulation; D005813:Genes, Synthetic; D007074:Immunoglobulin G / Q000235:genetics / Q000276:immunology; D007143:Immunoglobulin Heavy Chains / Q000235:genetics / Q000276:immunology; D007135:Immunoglobulin Variable Region / Q000235:genetics / Q000276:immunology; D007145:Immunoglobulin kappa-Chains / Q000235:genetics / Q000276:immunology; D008181:Lupus Nephritis / Q000235:genetics / Q000276:immunology*; D008285:Major Histocompatibility Complex; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C / Q000235:genetics / Q000276:immunology; D008810:Mice, Inbred C57BL / Q000235:genetics / Q000276:immunology; D008811:Mice, Inbred DBA / Q000235:genetics / Q000276:immunology; D008814:Mice, Inbred NZB / Q000235:genetics / Q000276:immunology; D008822:Mice, Transgenic
chemical_list: D000974:Antibodies, Antinuclear; D007074:Immunoglobulin G; D007143:Immunoglobulin Heavy Chains; D007135:Immunoglobulin Variable Region; D007145:Immunoglobulin kappa-Chains