Breathing Easier
UCLA researchers have joined the effort to establish
a connection between the residues of fossil fuel combustion and an epidemic
of respiratory allergies
 Two centuries ago,
“airway” diseases such as hay fever and allergic asthma were rare and mostly
minor afflictions. Today, according to Dr. Andrew Saxon, chief of
the UCLA School of Medicine’s Division of Clinical Immunology and Allergy,
approximately 40 percent of the world’s population is at risk. And, despite
vastly improved knowledge of the pathophysiology and treatment of allergic
asthma, that condition is not only more common, but also more severe than
ever before.
Intrigued by the history of the epidemic, Saxon and colleagues (Drs.
Oliver Hankinson, Harvey Herschman and André Nel) at the UCLA Asthma,
Allergy and Immunologic Disease Center began looking at possible underlying
causes. “Human genetics have changed trivially over 200 years,” says Saxon.
“The plants in our environment are not that different. The major change
has been industrialization.” In particular, the researchers were interested
in studies conducted in Japan suggesting that materials from fossil fuel
combustion could affect the mucous membranes in the lungs and nose, boosting
an allergic response. “We decided that if this were true, it would be very
important to bring molecular immunology, molecular biology and molecular
genetics to bear on the issue,” Saxon says.
Saxon, whose own background is in research on the structure of the genes
that make the proteins that cause allergies in humans, began to study the
impact of airborne pollutants on these genes as a way of accounting for
the increasing incidence and severity of asthma. He chose to focus on diesel
exhaust particles, not because he thought it likely that they were the
only culprit (although as less coal is burned, they are, in fact, an increasingly
important source of airborne particulates), but because diesel exhaust
can be measured in the environment and reproduced in a laboratory setting.
Diesel and other fossil fuel combustion products, known as xenobiotics,
carry chemicals which, once inside the airway, penetrate the cell membrane
and attach to a special aromatic hydrocarbon receptor, which is involved
in breaking down such materials. Saxon hypothesized that this process stimulates
the immune system so that, in the presence of these chemicals, an antigen
that the body might otherwise ignore triggers an allergic response.
In studies that began in the test tube and eventually involved volunteer
human subjects, Saxon found that among individuals who were sensitive to
a particular allergen, instilling the allergen, plus diesel exhaust particles,
in the nose in doses equivalent to breathing the air in Los Angeles for
one to three days produced a fivefold increase in total allergic protein
level and a 50 fold increase in the number of reaction inducing allergic
antibodies.
“We’re definitely not saying that if you’re in the emergency room with
an asthma attack, it was diesel particles that precipitated it,” Saxon
says. “But we do want to know how fossil fuel combustion products participate
in helping people make enough antibodies that they are now at risk of developing
clinical asthma or hay fever.”
Translating these observations into ways of addressing the problem is
the goal of Saxon’s center, only one of a handful funded by the National
Institutes of Health and the only one to receive joint funding from the
National Institute of Allergy and Infectious Diseases (NIAID) and the National
Institute of Environmental Health Sciences (NIEHS). Saxon credits leaders
such as Dr. Bob Goldstein at NIAID and Drs. Kenneth Olden and George Malindzak
Jr. at NIEHS for taking the initiative in combining forces to support this
important immunological research.
Saxon and the center’s other investigators are now attempting to define
and analyze the steps in the pathway leading from the body’s first encounter
with the foreign chemicals to the production of antibodies to allergic
reactions, in the hope that one day they will begin to discover treatments.
“In the future, we would like to find ways to prevent people who are already
allergic from having an increased response, or even to block at risk people
from becoming sensitized in the first place,” Saxon explains.
Saxon has studied the B cells that create the antibodies; Nel’s research
has focused on the T cells and macrophages that send the signals that control
the B cells. Herschman has examined the mechanisms underlying mast cells
— the destination of the antibodies and the cells whose activation results
in the observed allergic reaction — and Hankinson is an expert in the pathways
of the xenobiotic system. “We’ve all done our own basic research,” Saxon
says, “and now we’re bringing it together to focus on the larger issue
of how the environment affects these basic systems in a clinical setting.”
— D.G.
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