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Genetic Variant Reduces Immune Response, Yet Protects Against Atherosclerosis


Duke Health News 919-660-1306

DURHAM, N.C. -- An international team led by Duke University
Medical Center researchers has discovered that a genetic
variant of an immune system receptor appears to simultaneously
dampen the body's immune response to bacteria and other
microbial toxins and to provide some protection against
atherosclerosis, or clogging of the arteries. The scientists
believe their discovery suggests a possible new approach to
anti-atherosclerosis drugs.

The genetic variant, or polymorphism, occurs in one of a
family of 10 receptors known collectively as "Toll-like
receptors" (TLRs), reflecting the fact that the human receptors
resemble Toll receptors first discovered in flies. These TLRs
-- which are located on the surface of immune cells, heart
muscle cells, airway epithelial cells and cells lining blood
vessels -- are crucial to immune responses to bacteria. They
recognize a specific lipid on the surface of bacteria and
provide the first warning to the immune system that an invader
is present. The researchers estimate that the polymorphism of
the Toll-like receptor 4 (TLR4) they studied occurs in about 10
percent of the population.

"This particular polymorphism appears to attenuate the
receptor signaling ability and to diminish the inflammatory
response. Our results suggest that the diminished inflammatory
response is responsible for a decreased risk of
atherosclerosis," said Duke's David Schwartz, M.D., principal
investigator for the study, the results of which were published
today (July 18, 2002) in the New England Journal of Medicine.
"We were quite encouraged that the data were so compelling in
the degree to which this polymorphism is so protective.

"This represents a completely new mechanism involved in
atherosclerosis and cardiovascular disease, and it provides a
potential novel target for decreasing one's chances of
developing heart disease," Schwartz continued. "In addition to
using traditional means to reduce the risk of heart disease,
such as exercise, smoking cessation and lowering cholesterol,
in the future, it may also be possible to reduce risk by
influencing the activity of this receptor."

Theoretically, an agent or drug could be given to modulate
the activity of these receptors, Schwartz said, adding that
they will attempt to initiate clinical studies using TLR4
inhibitors on humans at high-risk for developing
atherosclerosis in the near future.

Toll-like receptors, which were only discovered two years
ago, appear to be the critical link in what is known as the
innate immune system, or the body's "first-responders." When
activated by a pathogen or bacteria, these receptors stimulate
the release of anti-microbial proteins, inflammatory cells and
other immune molecules. While this response is effective in
battling infections, Schwartz' findings suggest that these
agents also appear to play a role in the development of plaques
within blood vessels, the hallmark of atherosclerosis.

When the Toll-like receptors were discovered, Schwartz
wanted to know if there was a relationship between this innate
immune response and the process of atherosclerosis. To
determine if such a relationship existed, the team consulted
with an investigator in Austria and used data collected during
the Bruneck Study, which followed 810 patients in Italy from
1990 to 1995, with another five-year follow-up.

The Bruneck Study was a prospective survey of the natural
history of atherosclerosis, and what made the study population
interesting to the Duke researchers was that it included
detailed information of patients' immunological status, as well
as ultrasound studies of the major arteries in the neck.

Of the 810 patients, the Duke researchers found 55 to have
the TLR4 polymorphism.

"When compared to the other patients, those with the
polymorphism had lower levels of inflammatory immune proteins
known as cytokines, as well as other adhesion and inflammatory
molecules," Schwartz explained. "These patients also had a
substantially higher frequency of bacterial infections."

The researchers then examined the results of three different
ultrasound tests used to determine the degree to which the
carotid artery -- the main artery supplying oxygen-rich blood
to the brain -- was clogged in the affected patients. The
degree of clogging, or intimal thickening, is a commonly used
indicator for atherosclerosis.

"Whichever measure of atherosclerosis we used, the specific
polymorphism emerged as significant protective factor,"
Schwartz said. "Furthermore, all of these results were
virtually unchanged when we statistically adjusted for other
common cardio-vascular risk factors."

TLR4 is activated when it encounters lipopolysaccharides --
molecules that include both lipid and sugar components -- on
the surface of common bacteria, including Chlamydia pneumonias
and Helicobacter pylori, the most common bacteria implicated in
atherosclerosis. Lipopolysaccharides, the major component of
the cell walls of many common bacteria, are found circulating
in variable levels in virtually all healthy humans.

"The diminished levels of inflammation within blood vessels
and the enhanced risk of severe bacterial infections found in
the patients with the TLR4 polymorphism are clear indications
of a dampened innate immune system," Schwartz said.
"Conversely, people without the polymorphism would have fewer
bacterial infections, but would be at higher risk for

The research was supported by the National Institutes of
Health (NIH), the Department of Veterans Affairs, the
Pustertaler Verein zur Pravention von Herz und
HirngefaBerkrankungen, the Sanitatacinhelt Ost, and the
Assesaorat fir Gesundheit.

Other members of the team included: from University Clinic,
Innsbruck, Austria, Stefan Kiechl, M.D., Markus Reindl, Ph.D.,
Johann Willeit, M.D., and Christian Wiedermann, M.D.; Eva
Lorenz, Ph.D., Wake Forest University Medical School; Friedrich
Oberhollenzer, Bruneck Hospital, Italy; and Enzo Bonora, M.D.,
University of Verona, Italy.

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