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]

How to get your NIHRO1 grant renewed!

Yikes! It's that time again...our once 5 year grant has 2 and a half years to go, time to think about renewal!  What you say? But you're only half-way through - but think about it - the time from submission to actually getting the $ is 9 months!  And that's assuming you get it funded the first time -- and usually, that's not a safe assumption to make, for anyone [OK good on you people who get everything you put in funded, I'm happy for you!] - as we probably are not the only people in this situation, I thought I would post this link to a very helpful website -- the NIH NIAID has a newsletter covering exactly these topics, and let's face it, if anyone is going to provide good advice, it's likely to be the NIH...read all about it here.

Congratulations Jenn!

A big congrats to Jennifer Gregg in the lab, for placing second in the poster competition at the SBUR meeting in Baltimore over the weekend!  Jenn's poster was regarding the mechanism by which PSMA increases uptake of monoglutamated folates - i.e. folic acid and methotrexate -- Congrats once again Jenn!

Jennifer Gregg, and her winning poster August 2012

Activation of innate anti-viral immune response genes in symptomatic benign prostatic hyperplasia

A big CONGRATS to Allison Atwood-Madigan in the lab, the above paper has just been accepted for publication in Genes & Immunity (a Nature journal)!  Bring on the celebratory laser-tag!

Magical Beets?

We all know you should eat your veggies, and here's another reason -- according to this paper by Hobbs et al., beets (called beetroot down under), pretty much instantly lower blood pressure after they are ingested! My hubby was so excited that he bought a dehydrator to start making beet-chips, which aren't too bad - but these veggies look great in salads or with a sunday roast -- and, unlike some food studies, you don't have to eat 50 beets to get the effect - just one 100g beet should do it!  Try to beet that!

Blood pressure-lowering effects of beetroot juice and novel beetroot-enriched bread products in normotensive male subjects.

Hobbs DA, Kaffa N, George TW, Methven L, Lovegrove JA.

Source

Hugh Sinclair Unit of Human Nutrition, Department of Food and Nutritional Sciences, School of Chemistry, Food and Pharmacy, The University of Reading, Whiteknights, PO Box 226, Reading, Berks RG6 6AP, UK.

Abstract

A number of vegetables have a high nitrate content which after ingestion can be reduced to nitrite by oral bacteria, and further to vasoprotective NO endogenously. In the present study, two separate randomly controlled, single-blind, cross-over, postprandial studies were performed in normotensive volunteers. Ambulatory blood pressure (BP) was measured over a 24 h period following consumption of either four doses of beetroot juice (BJ), 0, 100, 250 and 500 g (n 18), or three bread products, control bread (0 g beetroot), red beetroot- and white beetroot-enriched breads (n 14). Total urinary nitrate/nitrite (NOx) was measured at baseline, and at 2, 4 and 24 h post-ingestion. BJ consumption significantly, and in a near dose-dependent manner, lowered systolic BP (SBP, P < 0·01) and diastolic BP (DBP, P < 0·001) over a period of 24 h, compared with water control. Furthermore, bread products enriched with 100 g red or white beetroot lowered SBP and DBP over a period of 24 h (red beetroot-enriched bread, P < 0·05), with no statistical differences between the varieties. Total urinary NOx significantly increased following the consumption of 100 g (P < 0·01), 250 g (P < 0·001) and 500 g BJ (P < 0·001) and after red beetroot-enriched bread ingestion (P < 0·05), but did not reach significance for white beetroot-enriched bread compared with the no-beetroot condition. These studies demonstrated significant hypotensive effects of a low dose (100 g) of beetroot which was unaffected by processing or the presence of betacyanins. These data strengthen the evidence for cardioprotective BP-lowering effects of dietary nitrate-rich vegetables.