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 Johns Hopkins Medicine
Media Relations and
Public Affairs
Media contact: David
March
410-955-1534
FOR IMMEDIATE
RELEASE: MONDAY, MAY 3, 2010
A CENTURY-OLD
PUZZLE COMES TOGETHER: SCIENTISTS ID POTENTIAL PROTEIN TRIGGER IN LUNG
DISEASE SARCOIDOSIS
Lung researchers at Johns Hopkins
have identified a possible protein trigger responsible for sarcoidosis,
a potentially fatal inflammatory disease marked by tiny clumps of
inflammatory cells that each year leave deep, grainy scars on the lungs,
lymph nodes, skin and almost all major organs in hundreds of thousands
of Americans.
The disorder, whose cause has been a
persistent mystery for nearly a century, strikes mostly young adults and
disproportionately affects African Americans.
The
link between sarcoidosis and overproduction of the suspected protein
trigger, called serum amyloid A, was revealed after a six-year
investigation encompassing more than two dozen laboratory experiments,
including some on diseased lung tissue samples from 86 patients in the
Baltimore area.
"The increase in production of serum
amyloid A explains for the first time how inflammation can persist in
the lungs without being triggered by an active infection," says study
senior investigator and pulmonologist David Moller, M.D., a professor at
the Johns Hopkins University School of Medicine. Moller is
also director of the sarcoidosis clinic at The Johns Hopkins
Hospital.
Study lead investigator Edward Chen, M.D.,
says the new findings also clear the path for developing drug treatments
or vaccines that can block serum amyloid A from binding to cell
receptors and kicking off inflammation.
In the short
term, however, Moller says his team has plans to use the study results
to create diagnostic tests that could better predict which people with
the disease are likely to heal on their own or are more likely to suffer
persistent inflammation, which can lead to scarring, difficulty
breathing, and heart failure that can only be fixed by lung
transplantation.
In a report published in February in
the American Journal of Respiratory and Critical Care Medicine, the
Johns Hopkins scientists described their research on what was behind the
microscopic clusters of inflamed tissue and white blood cells, or
granulomas, which are a defining feature of sarcoidosis.
Such lung lesions are not unique to sarcoidosis and
can be triggered by infections, such as in tuberculosis, which is often
confused with sarcoidosis. But unlike tuberculosis,
sarcoidosis is not an infectious disease, does not yield to antibiotics,
and is not limited to any particular organ, occurring as well in the
eyes, skin, brain, heart and liver.
Of particular
interest to researchers was the role played by so-called amyloids, a set
of proteins known to cause other persistent inflammatory conditions,
such as amyloidosis. Indeed, a different kind of amyloid has
been tied to plaques in the brain tissue of people with Alzheimer's
disease.
Key among the researchers' findings in
sarcoidosis patients was that serum amyloid A stood out because it was
heavily concentrated within the granulomas in diseased and scarred lung
tissue. Researchers found the protein a hundred to a thousand
times more widespread in sarcoidosis tissue samples than in samples from
people with tuberculosis, another granuloma-forming lung
disease. Similarly elevated amyloid levels were seen in
comparison tests with tissue samples from people with lung cancer and
Crohn's disease.
Further tests in patients' lung
cell cultures showed that adding serum amyloid A spiked production of at
least a half-dozen key inflammatory chemicals known to be involved in
damaging tissue.
In another series of experiments in
mice, the team discovered that granuloma formation in the lungs sped up
when the mice were given injections of synthetic serum amyloid
A. Mice had previously been injected with specially coated
plastic beads designed to trigger sarcoidosis-like lesions. Adding the
synthetic protein led to the same biochemical reactions in the mice as
observed in humans, suggesting to the researchers that serum amyloid A
played a key role in triggering sarcoidosis.
To better
understand how serum amyloid A might be driving granuloma formation, the
team used special antibodies to block various cell surface receptor
sites where the protein would bind to the white blood cells and spur
inflammation. Tests in human lung cells showed that blocking one
particular receptor, toll-like receptor-2 (TLR2), inhibited the
sustained inflammatory reaction typically associated with
sarcoidosis. But when left to bind on its own, without an
antibody blocking TLR2, the open receptor could attach to serum amyloid
A, and raised production of inflammatory chemicals would
ensue.
"Not only have we shown that serum amyloid A is a key
protein trigger in sarcoidosis, but we also have evidence that the
resulting inflammation is dependent on binding the protein at toll-like
receptor-2, which opens up a host of possibilities that drugs blocking
this binding site could prove an effective treatment for this disease,"
says Chen, an assistant professor at Johns
Hopkins.
Funding support for the report and research
was provided by the National Institutes of Health, the American Thoracic
Society, the Foundation for Sarcoidosis Research, the Life and Breath
Foundation, and the Hospital for the Consumptives of Maryland
(Eudowood.)
In addition to Moller and Chen, other
Johns Hopkins researchers involved in this study were Zhimin Song, M.D.;
Matthew Willett, B.S.; Shannon Heine, B.S.; Rex Yung, M.D.; Mark Liu,
M.D.; Steve Groshong, M.D., Ph.D.; Ying Zhang, M.D., Ph.D.; and Rubin
Tuder, M.D.
For additional information,
please go to:
http://www.hopkinsmedicine.org/pulmonary/about/faculty.html#Moller
http://ajrccm.atsjournals.org/content/vol181/issue4/index.shtml
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