Murine monoclonal anti-DNA antibodies penetrate cells, bind to nuclei, and induce glomerular proliferation and proteinuria in vivo.
The production of relatively high quantities of autoantibodies (autoAb) that react with DNA and other intranuclear antigens is characteristic of individuals with systemic lupus erythematosus and other autoimmune diseases. However, the capacity of these Ab to penetrate cells and induce functional perturbations in vivo is not well appreciated. To address this issue, monoclonal (m) anti-DNA Ab (mAb), derived from MRL-lpr/lpr and (NZB x SWR)F1 mice, were administered to normal mice, and the animals were examined for morphologic and functional abnormalities. A subset of five mAb produced intranuclear immunoglobulin deposits in multiple organs. Intranuclear immunoglobulin deposits were also observed after cross-linking the tissue before direct immunofluorescence and after i.v. injection of F(ab')2 fragments of one anti-DNA Ab. This phenomenon was reproducible and was only associated with this subset of autoAb. Furthermore, intranuclear deposits of anti-DNA Ab within glomeruli were associated with morphologic and functional abnormalities including: hypercellularity, epithelial foot process fusion, new fiber bundle formation within the mesangium suggestive of new collagen synthesis, and proteinuria. These results indicate that a subset of autoAb may penetrate cells in vivo to influence normal cellular and nuclear function and to contribute to functional and pathologic abnormalities in individuals with systemic lupus.
Vlahakos
D
D
Department of Medicine, New England Medical Center Hospital, Boston, MA.
Foster
M H
MH
Ucci
A A
AA
Barrett
K J
KJ
Datta
S K
SK
Madaio
M P
MP
D000818:Animals; D000974:Antibodies, Antinuclear / Q000378:metabolism / Q000502:physiology*; D000911:Antibodies, Monoclonal / Q000378:metabolism / Q000502:physiology*; D002467:Cell Nucleus / Q000378:metabolism; D006825:Hybridomas / Q000276:immunology; D007140:Immunoglobulin Fab Fragments / Q000378:metabolism / Q000502:physiology; D007678:Kidney Glomerulus / Q000166:cytology / Q000276:immunology*; D008180:Lupus Erythematosus, Systemic / Q000276:immunology; D051379:Mice; D008815:Mice, Inbred Strains; D008856:Microscopy, Fluorescence; D011507:Proteinuria / Q000276:immunology*
D000974:Antibodies, Antinuclear; D000911:Antibodies, Monoclonal; D007140:Immunoglobulin Fab Fragments