The influence of variable-region somatic mutations on the specificity and pathogenicity of murine monoclonal anti-DNA antibodies.
Antibodies to DNA (anti-DNA) occur prominently in systemic lupus erythematosus and provoke inflammatory damage in the kidneys. To determine the factors that confer pathogenicity on antibodies of this specificity, we investigated the in vitro and in vivo glomerular binding by members of four clonally related sets of monoclonal anti-DNA antibodies from lupus mice. Somatic mutations within the clonal sets enhanced binding to double-stranded DNA (dsDNA). Binding to permeabilized glomeruli in vitro was observed among affinity-purified preparations of these antibodies independent of specificity for dsDNA. In normal mice injected with hybridoma cell lines, nephritis as assessed by histology and immunofluorescence did not correlate with antibody affinity for DNA. By multivariate analysis, in vitro glomerular binding was the most predictive parameter of histologic outcome. These findings indicate that somatic mutations occurring during maturation of the autoimmune response do not necessarily enhance pathogenicity.
Gilkeson
G S
GS
Durham VA Medical Center, Duke University Medical Center, North Carolina 27705, USA.
Bernstein
K
K
Pippen
A M
AM
Clarke
S H
SH
Marion
T
T
Pisetsky
D S
DS
Ruiz
P
P
Lefkowith
J B
JB
D000595:Amino Acid Sequence; D000818:Animals; D000974:Antibodies, Antinuclear / Q000235:genetics / Q000633:toxicity*; D000911:Antibodies, Monoclonal; D000918:Antibody Specificity; D004247:DNA / Q000276:immunology*; D005260:Female; D006825:Hybridomas; D007135:Immunoglobulin Variable Region / Q000235:genetics*; D007678:Kidney Glomerulus / Q000276:immunology / Q000473:pathology; D008181:Lupus Nephritis / Q000209:etiology / Q000276:immunology*; D051379:Mice; D008807:Mice, Inbred BALB C; D008811:Mice, Inbred DBA; D008817:Mice, Mutant Strains; D008969:Molecular Sequence Data; D009154:Mutation; D017386:Sequence Homology, Amino Acid
D000974:Antibodies, Antinuclear; D000911:Antibodies, Monoclonal; D007135:Immunoglobulin Variable Region; D004247:DNA