Aberrant T cell ERK pathway signaling and chromatin structure in lupus.
Human systemic lupus erythematosus (SLE) is an autoimmune disease characterized by autoantibodies to nuclear components with subsequent immune complex formation and deposition in multiple organs. A combination of genetic and environmental factors is required for disease development, but how the environment interacts with the immune system in genetically predisposed hosts to cause lupus is unclear. Recent evidence suggests that environmental agents may alter T cell chromatin structure and gene expression through effects on DNA methylation, a repressive epigenetic mechanism promoting chromatin inactivation, to cause lupus in people with the appropriate genetic background. DNA methylation is regulated by ERK pathway signaling, and abnormalities in ERK pathway signaling may contribute to immune dysfunction in lupus through epigenetic effects on gene expression. This article reviews current evidence for epigenetic abnormalities, and in particular DNA demethylation, in the pathogenesis of idiopathic and some forms of drug-induced lupus, and how impaired ERK pathway signaling may contribute to the development of human lupus through effects on T cell DNA methylation.
Gorelik
Gabriela
G
Department of Medicine, University of Michigan, Ann Arbor, MI 48109-2200, USA.
Richardson
Bruce
B
D000818:Animals; D002843:Chromatin / Q000235:genetics / Q000378:metabolism; D042002:Chromatin Assembly and Disassembly / Q000276:immunology*; D019175:DNA Methylation / Q000276:immunology; D044127:Epigenesis, Genetic / Q000276:immunology; D048049:Extracellular Signal-Regulated MAP Kinases / Q000276:immunology / Q000378:metabolism*; D020022:Genetic Predisposition to Disease; D006801:Humans; D008180:Lupus Erythematosus, Systemic / Q000235:genetics / Q000276:immunology / Q000378:metabolism*; D028361:Mitochondrial Diseases / Q000201:enzymology / Q000276:immunology; D011493:Protein Kinase C / Q000378:metabolism; D015398:Signal Transduction / Q000276:immunology*; D013601:T-Lymphocytes / Q000276:immunology / Q000378:metabolism*
D002843:Chromatin; C089212:protein kinase D; D011493:Protein Kinase C; D048049:Extracellular Signal-Regulated MAP Kinases