Wednesday, January 24, 2007

Cracking open the black box of autoimmune disease

I read news of this discovery earlier this week, and was for the first time encouraged by progress being made in the field of autoimmunity. In March 2005, the Autoimmune Diseases Coordinating Committee from the National Institutes of Health gave a progress update to Congress. Although type 1 diabetes is cited numerous times in the report, I read it wondering how practical (or useful) the committee's objectives were, such as their goal of quantifying and monitoring the burden of autoimmune diseases (maybe useful in getting Congress to fund the work), determining the causes underlying their growing prevalence (nice to know, but what's the practical use of this knowledge?). About the only part of the committee's objectives that I saw any immediate value in was in improving training, education, and the dissemination of information about the autoimmune diseases to health care professionals and the public.

However, this week, researchers at the Whitehead Institute for Biomedical Research, an organization closely affiliated with Massachusetts Institute of Technology, had some encouraging news. While the practical use of this discovery is unlikely to come along for years, it helps close the huge knowledge gap that exists in the field of immunology, which has direct implications for patients with type 1 diabetes (and 80 other autoimmune diseases), so I am reposting their summary below, as they could remove the post, but I wanted to capture it here for my readers.

CAMBRIDGE, Mass. (January 21, 2007) — 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, a team of scientists from 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," says Whitehead Member and MIT professor of biology Richard Young, senior author on the paper that will appear January 21 online in Nature. "With this new list of genes, we can now look for possible therapies with far greater precision."

"Autoimmune diseases take a tremendous toll on human health, but on a strictly molecular level, autoimmunity is a black box," says Whitehead Member Richard Young.

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 Richard Young's Whitehead 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 schematic represents the researchers' strategy to identify where Foxp3 physically interacts with the genome in T cells. The background is a microarray where the red probes reveal regions of DNA where Foxp3 is bound. Image: Tom DiCesare

"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," says Alexander Marson, a MD/PhD 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," says Young. "When we discover the molecular mechanisms that drive these conditions, we can migrate from treating symptoms to developing treatments for the disease itself."

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

- Written by David Cameron

Full Citation:

Nature, January 21, 2007, early online edition

"Foxp3 occupancy and regulation of key target genes during T-cell stimulation"

Authors: Alexander Marson(1,2), Karsten Kretschmer(6,7), Garrett M. Frampton(1,2), Elizabeth S. Jacobsen(1), Julia Polansky(6), Kenzie D. MacIsaac(3), Stuart S. Levine(1), Ernest Fraenkel(4,5), Harald von Boehmer(6,7) and Richard A. Young(1,2)

(1) Whitehead Institute for Biomedical Research, Cambridge, MA
(2) Department of Biology, Massachusetts Institute of Technology (MIT), Cambridge, MA
(3) Department of Electrical Engineering and Computer Science, Massachusetts Institute of Technology (MIT), Cambridge, MA
(4) Biological Engineering Division, Massachusetts Institute of Technology (MIT), Cambridge, MA
(5) Computer Science and Artificial Intelligence Laboratory, Massachusetts Institute of Technology (MIT), Cambridge, MA
(6) Department of Cancer Immunology and AIDS, Dana-Farber Cancer Institute, Boston, MA
(7) Department of Pathology, Harvard Medical School, Boston, MA

Whitehead Institute for Biomedical Research is a nonprofit, independent research and educational institution. Wholly independent in its governance, finances and research programs, Whitehead shares a close affiliation with Massachusetts Institute of Technology through its faculty, who hold joint MIT appointments.

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