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The Journal of Immunology
Article . 2007 . Peer-reviewed
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Lack of Chromatin and Nuclear Fragmentation In Vivo Impairs the Production of Lupus Anti-Nuclear Antibodies

Authors: Marc Monestier; Minoru Satoh; Sun Ah Kang; Lorenza Frisoni; Michael P. Madaio; Roberto Caricchio; Lenese McPhie;

Lack of Chromatin and Nuclear Fragmentation In Vivo Impairs the Production of Lupus Anti-Nuclear Antibodies

Abstract

AbstractNuclear autoantigens in systemic lupus erythematosus are thought to derive primarily from apoptotic cells, yet there is no direct evidence that interfering with apoptosis impairs the generation of lupus autoantibodies. Here we use a mouse model that lacks the endonuclease caspase-activated DNase (CAD), resulting in an absence of chromatin and nuclear fragmentation during apoptotic cell death. We show that in this mouse, production and release into circulation of chromatin is impaired after exposure to several apoptotic triggers, but that the absence of CAD does not interfere with upstream steps of apoptosis or immune system function. Finally we show that in CAD-mutant mice, impaired lupus autoimmunity is skewed toward known cytoplasmic components, and autoimmunity toward membrane autoantigens is preserved, while autoimmunity toward chromatin and other lupus nuclear targets is severely impaired or absent. We also show, as control, that the induction of experimental autoimmune encephalomyelitis is not affected by the absence of CAD. Thus, our work in vivo strongly suggests that apoptotic molecular steps during cell death generate nuclear autoantigens to sustain the specific autoimmune response in systemic lupus erythematosus.

Related Organizations
Keywords

Lipopolysaccharides, Mice, Knockout, Deoxyribonucleases, Terpenes, Apoptosis, DNA Fragmentation, Chromatin, Autoimmune Diseases, Mice, Inbred C57BL, Disease Models, Animal, Mice, Gamma Rays, Antibodies, Antinuclear, Immunoglobulin G, Animals, Lupus Erythematosus, Systemic, Cells, Cultured, Phospholipids

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    This indicator reflects the "current" impact/attention (the "hype") of an article in the research community at large, based on the underlying citation network.
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citations
This is an alternative to the "Influence" indicator, which also reflects the overall/total impact of an article in the research community at large, based on the underlying citation network (diachronically).
BIP!Citations provided by BIP!
popularity
This indicator reflects the "current" impact/attention (the "hype") of an article in the research community at large, based on the underlying citation network.
BIP!Popularity provided by BIP!
influence
This indicator reflects the overall/total impact of an article in the research community at large, based on the underlying citation network (diachronically).
BIP!Influence provided by BIP!
impulse
This indicator reflects the initial momentum of an article directly after its publication, based on the underlying citation network.
BIP!Impulse provided by BIP!
24
Average
Average
Top 10%
bronze