The pathogenesis of systemic lupus erythematosus (SLE) is incompletely understood.
Studies in both lupus animal models and human disease indicate a clear role for epigenetic
defects, particularly DNA methylation, in the pathogenesis of lupus. T-cell DNA from
active lupus patients is hypomethylated, which results in overexpression of methylation-regulated
genes, T-cell autoreactivity, and autoimmunity in vivo. Inducing an extracellular signal-regulated kinase (ERK) signaling defect in T cells
using a transgenic mouse model resulted in reduced DNA methyltransferase 1 (DNMT1)
expression, overexpression of methylation-sensitive genes, and anti-double-stranded
DNA (anti-dsDNA) antibody production. ERK signaling is known to be defective in lupus
T cells, and this defect is now explained by impaired T-cell protein kinase C (PKC)
delta activation. Herein, we discuss how defective epigenetic regulation is involved
in the pathogenesis of lupus, which includes both DNA methylation and histone modification
changes.
Abbreviations:
5-azaC (5-azacytidine), DNMT (DNA methyltransferase), dsDNA (double-stranded DNA), ERK (extracellular signal-regulated kinase), HATs (histone acetyltransferases), HDACs (histone deacetylases), IFN-γ (interferon-γ), IgG (immunoglobulin-G), IL (interleukin), MBD (methyl CpG binding domain), MECP2 (methyl-CpG-binding protein 2), MTR (methionine synthase), NO (nitric oxide), PKC (protein kinase C), SCLE (subacute cutaneous lupus erythematosus), SLE (systemic lupus erythematosus), SNP (single nucleotide polymorphism), TNF-α (tumor necrosis factor-α), TSA (trichostatin A)To read this article in full you will need to make a payment
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Article info
Publication history
Published online: November 17, 2008
Accepted:
October 26,
2008
Received in revised form:
October 23,
2008
Received:
September 25,
2008
Footnotes
Supported by NIH Grant P20-RR015577 from the National Center for Research Resources and NIH Grant R03AI076729 from the National Institute of Allergy and Infectious Diseases, as well as by funding from the Arthritis National Research Foundation and the University of Oklahoma College of Medicine.
Identification
Copyright
© 2009 Mosby, Inc. Published by Elsevier Inc. All rights reserved.
