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Friday, August 31, 2012

Lupus: (aka SLE) an Autoimmune disease induced by DNA demethylation

Since discovering that a friend had to quit her promising postgraduate degree at CMU because she had lupus, I have been interested in what could possibly cause such a debilitating downfall in such a young, healthy woman - as I read the scientific literature on the subject, it became clear that at the molecular level there is a methylation defect - that is there is demethylated DNA present in the patient --- we've seen demethylated DNA in several different disease states; Benign Prostatic Hyperplasia (our manuscript in press), cancer, and rheumatoid arthritis -- at a simplistic level, all these diseases have inflammation. Can demethylated DNA induce inflammation?  Does how the cell see that inflammation differ depending on the type of cell or tissue, and the epigenetic background of the patient?  I bet it does.  I could theorize forever but as action speaks louder than words...here's a paper I found today which describes the development of a novel model for Lupus (as scientists we need realistic models to test potential mechanisms and treatments) - drug induced lupus can be induced by drugs that  are known to inhibit DNA methylation, for example procainamide.  This model extends those findings and will help to further our understanding of what treatments may, if any, be able to stop the disease from progressing. 

Methods Mol Biol. 2012;900:169-80.

Murine models of lupus induced by hypomethylated T cells (DNA hypomethylation and lupus…).

Richardson B, Sawalha AH, Ray D, Yung R.

Source

University of Michigan and the Ann Arbor Veteran's Affairs Hospital, Ann Arbor, MI, USA, brichard@umich.edu.

Abstract

CD4+ T cell DNA hypomethylation may contribute to the development of drug induced and idiopathic human lupus. Inhibiting DNA methylation in mature CD4+ T cells causes MHC-specific autoreactivity in vitro. The lupus-inducing drugs hydralazine and procainamide also inhibit T cell DNA methylation and induce autoreactivity, and T cells from patients with active lupus have hypomethylated DNA and a similarly autoreactive T cell subset. Further, T cells treated with DNA methylation inhibitors demethylate the same sequences that demethylate in T cells from patients with active lupus. The pathologic significance of the autoreactivity induced by inhibiting T cell DNA methylation has been tested by treating murine T cells in vitro with drugs which modify DNA methylation, then injecting the cells into syngeneic female mice. Mice receiving CD4+ T cells demethylated by a variety of agents including procainamide and hydralazine develop a lupus-like disease. Further, transgenic mice with an inducible T cell DNA methylation defect also develop lupus-like autoimmunity. This chapter describes the protocols for inducing autoreactivity in murine T cells in vitro and for inducing autoimmunity in vivo using an adoptive transfer approach or transgenic animal models.
PMID:
22933069
[PubMed - in process]

1 comment:

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