Good Cellular Defense May Be Best Offense Against Type1
Diabetes
By Jason Socrates
Bardi
A group of scientists at The Scripps Research Institute (TSRI)
have shown that if a certain type of cell in the pancreas
can defend itself against one particular virus, the owner
of that pancreas will not get diabetes.
Infection and loss of such insulin-producing "beta cells,"
residing in the Islets of Langerhans of the pancreas, is the
cause of the chronic autoimmune disease Type 1 diabetes.
"Our goal is to understand the causes of Type 1 diabetes,"
says TSRI Professor of Immunology Nora Sarvetnick, who led
the study. "The idea is that we might be able to go on and
design preventative therapies."
What Sarvetnick's team has now shown at TSRI, which is home
to one of the largest basic Type 1 diabetes research programs
in the world, is that the antiviral defenses undertaken by
beta cells is critical for the survival of this cell type
even after the body survives a viral infection.
Type-1 (insulin-dependent) diabetes mellitus is a chronic
metabolic disease that occurs when beta cells in the pancreas,
the body's source of insulin, are destroyed. The insulin produced
by these cells is responsible for regulating blood glucose
levels, which cells normally ingest to provide energy for
metabolic processes.
The therapy of choice for the disease is to inject insulin,
and before the discovery and isolation of insulin in the 1920s,
having this type of diabetes meant certain death. Though insulin
is a reasonable treatment, Type 1 diabetes is still a chronic
infection for which there is no prevention and no cure. It,
along with the more common Type 2 diabetes, is one of the
leading causes of blindness and kidney disease in the world
and one of the most costly health problems in the United States.
The agent that triggers the onset of Type 1 diabetes is
believed to be a common virus that infects cells in the pancreas,
since patients who have recently developed the disease often
have antibodies against this virus. And there are also genetic
and other environmental factors, only some of which are known,
that contribute to the development of Type 1 diabetes.
During the viral infection, the body makes an adaptive immune
response, and cytotoxic T lymphocytes selectively target and
eliminate cells that are infected with the virus.
Diabetes develops when the killing proceeds out of control,
and the T cells become autoreactive—targeting the person's
own insulin-producing b cells. In Type 1 diabetes, T cells
attack and kill all the insulin-producing cells in the body,
causing a depletion of these cells in the pancreas and of
insulin in the bloodsteam.
Without insulin, the glucose in the bloodstream increases
and is maintained at levels much greater than normal. Over
time, this can lead to nerve and kidney damage, reduced eyesight,
and an increased risk of developing heart disease and vascular
degeneration.
Sarvetnick's group has shown that the beta cells play a
role in their own destiny—they can survive the infection
if they are able to detect soluble proteins called Type1 interferons.
"When you get infected with the virus, the body reacts by
producing Type1 interferons," says Research Associate Malin
Flodström, who is first author on the paper.
"And," she says, "that should signal the b cells to respond."
During this response, the beta cells in the pancreas start
producing proteins that send the cells into an antiviral state.
Flodström, Sarvetnick, and their colleagues showed that
if the cells lose the ability to make this response, they
disappear from the body once they are infected.
In transgenic "knockout" models the team developed, which
cannot detect the signal from the interferons, an infection
with the virus causes diabetes 95 percent of the time. In
normal models, the virus alone does not cause disease because
the cells are able to respond to the interferons and protect
themselves against the virus.
Similarly, most individuals' beta cells are able to sense
interferons and protect themselves against the virus.
If a way can be found to provide people who are at risk
of developing diabetes with the tools that will enable their
pancreatic beta cells to defend themselves during a viral
infection, the team believes Type1 diabetes may become a preventable
disease.
The article, "Target cell defense prevents the development
of diabetes after viral infection" is authored by Malin Flodström,
Amy Maday, Deepika Balakrishna, Mary Malo Cleary, Akihiko
Yoshimura, and Nora Sarvetnick and appears in the April 2002
issue of the journal Nature Immunology.
The article and a separate commentary are available online
at http://www.nature.com/ni/.
The research was funded by the National Institutes of Health
and the Juvenile Diabetes Research Foundation.
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