Cracking open the black box of autoimmune
disease
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 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.
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