Ligand recognition by murine anti-DNA autoantibodies. II. Genetic analysis and pathogenicity.
Although anti-DNA autoantibodies are an important hallmark of lupus, the relationships among anti-DNA structure, reactivity, and pathogenicity have not been fully elucidated. To further investigate these relationships, we compare the variable genes and primary structure of eight anti-DNA mAbs previously obtained from an MRL/MpJ-lpr/lpr mouse along with the ability of three representative mAbs to induce nephritis in nonautoimmune mice using established adoptive transfer protocols. One monospecific anti-single-stranded (ss) DNA (11F8) induces severe diffuse proliferative glomerulonephritis in nonautoimmune mice whereas another anti-ssDNA with apparently similar in vitro binding properties (9F11) and an anti-double-stranded DNA (4B2) are essentially benign. These results establish a murine model of anti-DNA-induced glomerular injury resembling the severe nephritis seen in lupus patients and provide direct evidence that anti-ssDNA can be more pathogenic than anti-double-stranded DNA. In vitro binding experiments using both protein-DNA complexes and naive kidney tissue indicate that glomerular localization of 11F8 may occur by recognition of a planted antigen in vivo. Binding to this antigen is DNase sensitive which suggests that DNA or a DNA-containing molecule is being recognized.
Swanson
P C
PC
Department of Chemistry, University of Michigan, Ann Arbor, 48109-1055, USA.
Yung
R L
RL
Blatt
N B
NB
Eagan
M A
MA
Norris
J M
JM
Richardson
B C
BC
Johnson
K J
KJ
Glick
G D
GD
D000595:Amino Acid Sequence; D000818:Animals; D000974:Antibodies, Antinuclear / Q000235:genetics* / Q000276:immunology*; D000911:Antibodies, Monoclonal / Q000235:genetics* / Q000276:immunology*; D001483:Base Sequence; D003001:Cloning, Molecular; D004247:DNA / Q000235:genetics / Q000276:immunology*; D017931:DNA Primers / Q000235:genetics; D005803:Genes, Immunoglobulin; D006825:Hybridomas / Q000276:immunology; D007135:Immunoglobulin Variable Region / Q000235:genetics; D007668:Kidney / Q000276:immunology / Q000473:pathology; D008024:Ligands; D008181:Lupus Nephritis / Q000209:etiology / Q000235:genetics / Q000276:immunology; D051379:Mice; D008817:Mice, Mutant Strains; D008854:Microscopy, Electron; D008969:Molecular Sequence Data; D017386:Sequence Homology, Amino Acid; D012689:Sequence Homology, Nucleic Acid
D000974:Antibodies, Antinuclear; D000911:Antibodies, Monoclonal; D017931:DNA Primers; D007135:Immunoglobulin Variable Region; D008024:Ligands; D004247:DNA