Lack of chromatin and nuclear fragmentation in vivo impairs the production of lupus anti-nuclear antibodies

Lorenza Frisoni, Lenese McPhie, Sun Ah Kang, Marc Monestier, Michael Madaio, Minoru Satoh, Roberto Caricchio

Research output: Contribution to journalArticle

24 Scopus citations

Abstract

Nuclear 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.

Original languageEnglish (US)
Pages (from-to)7959-7966
Number of pages8
JournalJournal of Immunology
Volume179
Issue number11
DOIs
StatePublished - Dec 1 2007

ASJC Scopus subject areas

  • Immunology and Allergy
  • Immunology

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    Frisoni, L., McPhie, L., Kang, S. A., Monestier, M., Madaio, M., Satoh, M., & Caricchio, R. (2007). Lack of chromatin and nuclear fragmentation in vivo impairs the production of lupus anti-nuclear antibodies. Journal of Immunology, 179(11), 7959-7966. https://doi.org/10.4049/jimmunol.179.11.7959