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Microarray studies used for finding genes involved in autoimmune disease

Posted Sep 12 2008 4:39pm

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.”
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 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.”

Filed under: Clinical microarrays, clinical diagnostics, gene expression, genetics, genotyping, microarray

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