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Dr. Dieker, Mr. Fransen, and Ms van Bavel contributed equally to this work.
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Research Article
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Apoptosis-induced acetylation of histones is pathogenic in systemic lupus erythematosus
Article first published online: 25 MAY 2007
DOI: 10.1002/art.22646
Copyright © 2007 by the American College of Rheumatology
Additional Information
How to Cite
Dieker, J. W., Fransen, J. H., van Bavel, C. C., Briand, J.-P., Jacobs, C. W., Muller, S., Berden, J. H. and van der Vlag, J. (2007), Apoptosis-induced acetylation of histones is pathogenic in systemic lupus erythematosus. Arthritis & Rheumatism, 56: 1921–1933. doi: 10.1002/art.22646
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Dr. Dieker, Mr. Fransen, and Ms van Bavel contributed equally to this work.
Publication History
- Issue published online: 25 MAY 2007
- Article first published online: 25 MAY 2007
- Manuscript Accepted: 16 FEB 2007
- Manuscript Received: 24 APR 2006
Funded by
- Dutch Kidney Foundation. Grant Numbers: C99.1826, C05.2119
- PhD program of the Radboud University Nijmegen Medical Centre
- Abstract
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Abstract
Objective
In systemic lupus erythematosus (SLE), inadequate removal of apoptotic cells may lead to challenge of the immune system with immunogenic self antigens that have been modified during apoptosis. We undertook this study to evaluate whether apoptosis-induced histone modifications are targets for the immune system in SLE.
Methods
The epitope of KM-2, a monoclonal antihistone autoantibody derived from a lupus mouse, was mapped by random peptide phage display. The reactivity of KM-2 and plasma with (acetylated) histone H4 (H4) peptides and with nonapoptotic, apoptotic, and hyperacetylated histones was determined by immunofluorescence staining, enzyme-linked immunosorbent assay, and Western blotting.
Results
KM-2 recognized apoptosis-induced acetylation of H4 at lysines 8, 12, and 16. The majority of plasma samples from SLE patients and lupus mice showed higher reactivity with triacetylated H4 peptide (residues 1–22) and with hyperacetylated and apoptotic histones than with nonacetylated H4 peptide and normal histones. Importantly, administration of triacetylated H4 peptide to lupus-prone mice before disease onset accelerated the disease by enhancing mortality and aggravating proteinuria, skin lesions, and glomerular IgG deposition, while the nonacetylated H4 peptide had no pathogenic effect. The delayed-type hypersensitivity response in lupus mice against the triacetylated H4 peptide was higher than that against the nonacetylated H4 peptide. Bone marrow–derived dendritic cells (DCs) cultured in the presence of hyperacetylated nucleosomes showed increased expression/production of CD40, CD86, interleukin-6 (IL-6), and tumor necrosis factor α compared with DCs cultured in the presence of normal nucleosomes. Finally, DCs cultured in the presence of hyperacetylated nucleosomes were able to activate syngeneic T cells, because IL-2 production increased.
Conclusion
Apoptosis-induced acetylation of nucleosomes may represent an important driving force in the development of lupus.