Plasma levels of nucleosomes and nucleosome-autoantibody complexes in murine lupus: effects of disease progression and lipopolyssacharide administration

Arthritis Rheum. 2001 Jun;44(6):1320-30. doi: 10.1002/1529-0131(200106)44:6<1320::AID-ART224>3.0.CO;2-X.

Abstract

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.

Conclusion: 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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Age Factors
  • Animals
  • Antibodies, Antinuclear / blood
  • Antigen-Antibody Complex / blood
  • Cell Count
  • Disease Models, Animal
  • Disease Progression
  • Dose-Response Relationship, Immunologic
  • Enzyme-Linked Immunosorbent Assay
  • Escherichia coli / immunology
  • Immunoglobulin G / immunology
  • Lipopolysaccharides / pharmacology
  • Lupus Erythematosus, Systemic / blood*
  • Lymphocyte Activation
  • Mice
  • Mice, Inbred BALB C
  • Mice, Inbred CBA
  • Mice, Inbred MRL lpr
  • Nucleosomes / drug effects
  • Nucleosomes / immunology*
  • Thymus Gland / cytology
  • Thymus Gland / drug effects
  • Thymus Gland / immunology

Substances

  • Antibodies, Antinuclear
  • Antigen-Antibody Complex
  • Immunoglobulin G
  • Lipopolysaccharides
  • Nucleosomes