Discovery could lead to new therapies for autoimmune diseases


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David Cameron
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Autoimmune diseases such as type 1 diabetes, lupus and rheumatoid arthritis occur when the immune system fails to regulate itself. But researchers have not known precisely where the molecular breakdowns responsible for such failures occur.

Now, scientists from MIT, the Whitehead Institute and the Dana-Farber Cancer Institute have identified a key set of genes that lie at the core of autoimmune disease, findings that may help scientists develop new methods for manipulating immune system activity.

"This may shorten the path to new therapies for autoimmune disease," said Whitehead member and MIT professor of biology Richard Young, senior author on a paper that appeared Jan. 21 online in Nature. "With this new list of genes, we can now look for possible therapies with far greater precision."

The immune system is often described as a kind of military unit, a defense network that guards the body from invaders. Seen in this way, a group of white blood cells called T cells are the frontline soldiers of immune defense, engaging invading pathogens head-on.

These T cells are commanded by a second group of cells called regulatory T cells. Regulatory T cells prevent biological "friendly fire" by ensuring that the T cells do not attack the body's own tissues. Failure of the regulatory T cells to control the frontline fighters leads to autoimmune disease.

Scientists previously discovered that regulatory T cells are themselves controlled by a master gene regulator called Foxp3. Master gene regulators bind to specific genes and control their level of activity, which in turn affects the behavior of cells.

In fact, when Foxp3 stops functioning, the body can no longer produce working regulatory T cells. When this happens, the frontline T cells damage multiple organs and cause symptoms of type 1 diabetes and Crohn's disease. However, until now, scientists have barely understood how Foxp3 controls regulatory T cells because they knew almost nothing about the actual genes under Foxp3's purview.

Researchers in Young's lab, working closely with immunologist Harald von Boehmer of the Dana-Farber Cancer Institute, used a DNA microarray technology developed by Young to scan the entire genome of T cells and locate the genes controlled by Foxp3. There were roughly 30 genes found to be directly controlled by Foxp3 and one, called Ptpn22, showed a particularly strong affinity.

"This relation was striking because Ptpn22 is strongly associated with type 1 diabetes, rheumatoid arthritis, lupus and Graves' disease, but the gene had not been previously linked to regulatory T-cell function," said Alexander Marson, an M.D./Ph.D. student in the Young lab and lead author on the paper. "Discovering this correlation was a big moment for us. It verified that we were on the right track for identifying autoimmune related genes."

The researchers still don't know exactly how Foxp3 enables regulatory T cells to prevent autoimmunity. But the list of the genes that Foxp3 targets provides an initial map of the circuitry of these cells, which is important for understanding how they control a healthy immune response.

"Autoimmune diseases take a tremendous toll on human health, but on a strictly molecular level, autoimmunity is a black box," said Young. "When we discover the molecular mechanisms that drive these conditions, we can migrate from treating symptoms to developing treatments for the disease itself."

Other MIT authors of this paper are Garrett M. Frampton, a graduate student the Department of Biology; Kenzie D. MacIsaac, a graduate student in the Department of Electrical Engineering and Computer Science; and Ernest Fraenkel, an assistant professor in the Division of Biological Engineering who is also affiliated with MIT's Computer Science and Artificial Intelligence Laboratory.

This work was supported by a donation from E. Radutsky and by the Whitaker Foundation and the National Institutes of Health.

A version of this article appeared in MIT Tech Talk on January 24, 2007 (download PDF).


Topics: Bioengineering and biotechnology, Genetics, Health sciences and technology

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