Failure to Maintain T Cell DNA Methylation and Chromatin Structure Contributes to Human Lupus

  • Donna Ray
  • Bruce Richardson
Chapter

5. Conclusions

The studies summarized in this chapter demonstrate that the failure to maintain DNA methylation patterns in mature CD4+ T cells causes aberrant expression of several methylation-sensitive genes, including LFA-1, perforin, CD70, and likely others, and that their overexpression alters T cell function, promoting autoreactivity, monocyte/macrophage killing, and B cell overstimulation. Furthermore, T cells experimentally demethylated with DNA methyltransferase or ERK signaling pathway inhibitors cause a lupus-like disease in murine models. Procainamide and hydralazine are DNA methylation inhibitors and cause a lupus-like disease in genetically susceptible individuals. Patients with idiopathic lupus have hypomethylated DNA, overexpress the same genes due to the same changes in DNA methylation patterns as in the methylation inhibition model, and demonstrate identical changes in CD4+ T cell function including autoreactive, perforin-mediated monocyte killing and B cell overstimulation. Thus, similar changes in DNA methylation and chromatin structure likely contribute to the pathogenesis of autoimmunity in the DNA hypomethylation model as in idiopathic lupus. The DNA hypomethylation model may also provide an approach to predict additional aberrantly expressed genes in human lupus T cells, since CD11a, perforin, and CD70 were predicted by this model. Finally, these studies also suggest that environmental agents may act by mechanisms analogous to those seen in DIL, triggering changes in chromatin structure and affecting gene expression through signaling inhibition or direct DNA methyltransferase inhibition. Clearly, there is a fundamental role for a failure to maintain DNA methylation patterns and chromatin structure in this disease.

Keywords

Systemic Lupus Erythematosus Systemic Lupus Erythematosus Disease Activity Index Immune Complex Glomerulonephritis Idiopathic Lupus 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.
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Copyright information

© Springer Science+Business Media, Inc. 2005

Authors and Affiliations

  • Donna Ray
    • 1
  • Bruce Richardson
    • 1
  1. 1.Department of MedicineUniversity of Michigan

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