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New Finding Sheds Light on Mechanism of Inflammation in Lupus, Other
Disorders (September 2003)

September 4, 2003, Durham, NC -- New insights into how the body
eliminates dead cells could lead to new approaches for treating
conditions including lupus and cancer, or for preventing infections
following trauma. Researchers at Duke University Medical Center and the
Durham Veterans Administration Hospital say the specialized cells that
clear dead cells from the body have a much more complicated -- and
important -- role than scientists previously understood.

Most human cells die through a process known as apoptosis, or
"programmed cell death," and are rapidly removed from the body. In
contrast, necrotic death occurs when cells die from injury or disease.
Increased amounts of DNA from dead cells can be measured in the blood
following a wide range of medical events including trauma, heart
attacks, blood clots to the lung and chemotherapy treatment. Best known
as the molecule of heredity, DNA may perform other activities when it is
released from dead cells and appears in the blood.


Dead cells are cleared from the body by macrophages, scavenger cells of
the immune system. When macrophages do not remove dead cells, the
contents of the dead cells, including the DNA, can trigger a response
from the immune system, which may eventually weaken the body and leave
it susceptible to infection, a common complication following trauma. For
people with lupus, the contents of the dead cells, especially DNA, may
form immune complexes with antibodies that can cause inflammation that
is not only painful but also damaging to organs such as the kidneys.

Scientists have long believed DNA from dead cells is present in the
bloodstream only when macrophages become overwhelmed with more dead
cells than they can remove. In other words, the contents of the dead
cells "overflow" from the macrophages. David Pisetsky, M.D., professor
of medicine and chief of the division of rheumatology and immunology at
Duke University Medical Center, and colleagues recently discovered this
may not be the case. The Duke team reports their findings, from studies
funded by the Alliance for Lupus Research, in the Sept. 15, 2003, issue
of the journal Blood.

The Duke team was surprised while performing a series of experiments to
determine whether administration of a large amount of apoptotic and
necrotic cells would cause an increased amount of DNA to appear in the
blood of mice. In their first experiment, the researchers found that
injecting mice with a large quantity of dead cells indeed resulted in
increased DNA in the mice's blood.

In the next experiment, they engineered mice lacking macrophages and
injected the mice with a large quantity of dead cells. Because
macrophages were not present to remove the dead cells, the team expected
to find all of the dead cell DNA in the bloodstream. Instead, they found
none.

"This result was totally unexpected, and caused us to step back and
consider how the macrophages function to remove cell waste," Pisetsky
said. Without macrophages, his team eventually theorized, dead cells
cannot be broken down efficiently enough for DNA to appear in the
bloodstream at a detectable level. Cells not processed by macrophages
and removed from the body may ac***ulate and cause inflammation.

"What we hypothesize is that uptake by macrophages is not just part of
the process, but is absolutely crucial to the appearance of DNA from
dead cells in the blood," Pisetsky said. "The macrophages can't be
bypassed by the dead cells, even if there is more cell DNA than they can
process."

According to the researchers, this would mean that DNA from dead cells
appears in the blood only when macrophages "fill" to capacity and
perhaps then die and release all of their contents, including the DNA
from the engulfed cells.

"If we are indeed correct," said Pisetsky, "then macrophages play a much
more crucial role than previously thought. This finding could
potentially have implications for the treatment of lupus and other
inflammatory conditions."

The researchers said macrophages might be reinforced to clear larger
amounts of dead cells, thus reducing the amount of DNA and other
cellular molecules that pass into the blood and cause inflammation.
"This mechanism could apply not only to lupus, but also to conditions
like cancer, where we often intentionally kill large numbers of cells
with chemotherapy and other treatments," said Pisetsky.

Likewise, bolstering macrophages could help prevent the immune response
following trauma, and thereby help the body maintain normal levels of
immunity to prevent subsequent infection.

The findings also may lend new insight to the function of current lupus
treatment with corticosteroids, the researchers said. "Corticosteroids
are one of the standard treatments for inflammation in lupus. We've
always thought the steroids worked by reducing inflammation, but it may
be that, in fact, they strengthen the macrophages and prevent the
inflammatory response from beginning," said Pisetsky.

http://www.thyroid-info.com/autoimmune/inflammation.htm