Scientists at Johns Hopkins have outlined a new path
for potential therapies to combat
inflammation associated with sinusitis and asthma based on
a new understanding of the body's earliest
immune response in the nose and sinus cavities.
Researchers say their findings, published in the May
edition of The Journal of Allergy and
Clinical Immunology, are the first evidence describing
how viral agents, such as the rhinovirus
responsible for the common cold, can kick-start the body's
mobilization of immune white blood cells in
the moist, mucous membrane lining of the nasal passages.
While such responses are key to maintaining health in
the face of pathogens, they can also
become a source of illness due to resulting inflammation.
This can lead to potentially lifelong problems,
including tissue swelling, nasal polyp formation, sneezing,
stuffy and runny nose, sore throat, cough,
headache, chills, fever and breathing difficulties.
Thus, blocking these reactions, the re-searchers point
out, could interrupt the cascade of feel-
awful symptoms that ensue.
The focus of the study is B7-related proteins, called
B7 homologs, which trip white blood cell
response in a pathogen attack.
Using purified cold virus and its genetic material as
bait, the scientists found that production
of two B7 homologs spiked in response; levels of B7-H1
jumped almost ninefold, and levels of B7-DC
tripled.
Until now, says senior study investigator Jean Kim,
viruses were known to reside in and infect
the physical epithelium, invading surface membrane cells
and revving up the immune system's main
blood cell defenses, "but no one knew the major steps
involved in or precisely how this immune
response was triggered."
"The inside surface of our nose and sinuses is much
more than a protective cover, and we have
good scientific evidence to show that epithelial cells on
these mucosal membranes are very powerful
mediators — middlemen — in diseases that result
in inflammation," she said. An assistant professor at
the School of Medicine and an expert in the molecular
origins of inflammation, Kim is also an authority
on nasal and sinus infections.
Moreover, she notes, study results demonstrate how the
body's immune system is
interconnected, where one key part, the physical lining
that filters out and captures invading viruses
and environmental allergens, can trigger the other key
part, which leads to targeted white blood cell
action.
"Now that we have a better understanding of the immune
pathway, we can start to develop
therapies that could potentially block the triggering
reactions for sinusitis and asthma, which are both
made worse when people are infected with the common cold
virus," she said.
Sinusitis is the most common respiratory complaint in
the United States. The condition is often
linked with asthma, which affects more than 30 million
people, 9 million of them children. Each year,
62 million Americans catch a cold.
The study also explains a common failure in current
therapy.
According to Kim, nasal and oral steroids are
frequently prescribed for many of the 15 percent
of the American adult population who suffer from sinusitis,
nasal polyps or asthma. Steroids
complement drugs taken for symptomatic relief, such as
decongestants and pain relievers.
But corticosteroid drugs, she says, do not work for
everyone, and their effectiveness often
wanes over time.
This may be related to the B7 homolog triggers in the
mucous membranes, Kim says, as study
results showed that corticosteroid therapy does not fully
shut down or prevent their overproduction.
In the study's first set of experiments, researchers
found that levels of two of five key
proteins tested, B7-H1 and B7-DC, rose sharply after
samples of nasal cell concentrate were exposed
to genetic material from cold viruses. Spiked production
was detected using antibodies chemically
tagged to glow when bonded to a specific B7 homolog.
However, when researchers pretreated the cell
scrapings with a well-known anti-inflammatory
corticosteroid called flucticasone propionate, the drug
failed to stop overproduction of either B7-H1
or B7-DC.
In the final set of study experiments, six adult
volunteers were infected with the cold virus and
monitored for variations in their immune response during
infection, which typically lasts a week to 10
days.
Analysis of daily scrapings of surface cells lining
the nose showed that production of B7-H1 and
B7-DC peaked on the second and third days, when cold
symptoms were also at their worst. These
protein levels, as a measure of severity of the immune
response, dropped quickly afterward, and at the
same time as scores of symptom severity went down. It was
this evidence, Kim says, that verified the
triggering connection between the cold virus and the immune
white cell response inside the nose and
sinuses.
Kim says that researchers' next steps are to analyze
the biological control mechanisms for
producing the B7 homologs in the nasal lining, and to map
out any chemical interactions that result, to
look for ways of breaking the cycle of inflammation
involved in sinusitis, asthma and colds.
The study, which ran from 2003 to 2007, was funded by
the National Institutes of Health and
the Flight Attendant Medical Research Institute. Sinusitis
afflicts thousands of fight attendants who
were exposed to secondhand smoke before smoking was banned
on airlines in the late 1980s.
In addition to Kim, Johns Hopkins investigators
involved in this research were Lowella Heinecke
and Scherer Sanders. Further assistance was provided by
David Proud, of the University of Calgary;
and Robert Schleimer, of Northwestern University's Feinberg
School of Medicine.