Contribution of major histocompatibility complex (MHC) to upregulation of anti-DNA antibody in transgenic mice.
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)
Song
Y W
YW
Department of Medicine, University of California, Los Angeles 90024.
Tsao
B P
BP
Hahn
B H
BH
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
D000974:Antibodies, Antinuclear; D007074:Immunoglobulin G; D007143:Immunoglobulin Heavy Chains; D007135:Immunoglobulin Variable Region; D007145:Immunoglobulin kappa-Chains