Plasma levels of nucleosomes and nucleosome-autoantibody complexes in murine lupus: effects of disease progression and lipopolyssacharide administration.
OBJECTIVE
To evaluate the effect of disease progression and lipopolysaccharide (LPS) administration on the presence of nucleosomes, antinucleosome reactivity, and nucleosome-Ig complexes in the circulation of MRL and control mice.


METHODS
Plasma samples from lupus-prone (MRL/lpr and MRL/+) and control (CBA, Swiss, and BALB/c) mice were tested in enzyme-linked immunosorbent assays for the presence of nucleosomes, antinucleosome antibodies, and nucleosome-Ig complexes. Nucleosome kinetics, apoptosis induction, and phagocytosis of apoptotic cells were also analyzed in MRL/lpr, MRL/+, and CBA control mice after a single injection of LPS or phosphate buffered saline.


RESULTS
Nucleosomes were found in the circulation of MRL/lpr and MRL/+ mice from week 4 onward. Nucleosomes were also detected in young control mice, but with increasing age, the nucleosomes disappeared. Antinucleosome antibodies, nucleosome-Ig complexes, and albuminuria were found only in the MRL/lpr mice. LPS administration led to a significant increase in circulating nucleosomes (3-8-fold) in all strains tested. In only the MRL/lpr mice was this increase followed by a significant decrease in antinucleosome titers and an increase in nucleosome-Ig complexes. The number of apoptotic cells in the thymus after LPS was significantly higher in the MRL/lpr mice than in the MRL/+ and CBA control mice. LPS caused a profound reduction (50-70%) of the phagocytosis of apoptotic cells by peritoneal macrophages, which was comparable for all strains.


CONCLUSIONS
In MRL lupus-prone mice, nucleosomes are persistently present in the circulation, whereas in control mice, nucleosomes are present only at a young age. The formation of antinucleosome antibodies and nucleosome-Ig complexes is a characteristic feature of MRL/lpr mice. LPS administration increases systemic nucleosome release due to an enhancement of apoptosis and a decrease in the clearance of apoptotic cells.
Licht
R
R
University Medical Center Nijmegen, The Netherlands.
van Bruggen
M C
MC
Oppers-Walgreen
B
B
Rijke
T P
TP
Berden
J H
JH
D000367:Age Factors; D000818:Animals; D000974:Antibodies, Antinuclear / Q000097:blood; D000936:Antigen-Antibody Complex / Q000097:blood; D002452:Cell Count; D004195:Disease Models, Animal; D018450:Disease Progression; D004306:Dose-Response Relationship, Immunologic; D004797:Enzyme-Linked Immunosorbent Assay; D004926:Escherichia coli / Q000276:immunology; D007074:Immunoglobulin G / Q000276:immunology; D008070:Lipopolysaccharides / Q000494:pharmacology; D008180:Lupus Erythematosus, Systemic / Q000097:blood*; D008213:Lymphocyte Activation; D051379:Mice; D008807:Mice, Inbred BALB C; D008808:Mice, Inbred CBA; D019463:Mice, Inbred MRL lpr; D009707:Nucleosomes / Q000187:drug effects / Q000276:immunology*; D013950:Thymus Gland / Q000166:cytology / Q000187:drug effects / Q000276:immunology
D000974:Antibodies, Antinuclear; D000936:Antigen-Antibody Complex; D007074:Immunoglobulin G; D008070:Lipopolysaccharides; D009707:Nucleosomes