Activating a protein found on some immune cells seems to
halt the cells' typical job of spewing
out substances that launch allergic reactions, a study by Johns
Hopkins researchers suggests. The
findings could eventually lead to new treatments for allergic
reactions ranging from annoying bouts of
hay fever to deadly asthma attacks.
Previous studies by Bruce Bochner and his colleagues at the
Johns Hopkins Asthma and Allergy
Center had zeroed in on the protein, Siglec-8, as an important
player in allergic reactions. This protein
is found on the surfaces of some types of immune cells, namely
eosinophils, basophils and mast cells,
which have diverse but cooperative roles in normal immune
function and allergic diseases. Eosinophils
directly combat foreign invaders, such as parasites. Basophils
and mast cells store and release
substances such as histamine, prostaglandins and cytokines, which
signal other immune system cells to
ready for battle.
When functioning correctly, these cells are a valuable aid
to keeping the body healthy and
infection-free. However, in allergic reactions and asthma
attacks, the cells unleash an overwhelming
response that typically harms the body more than it helps.
The researchers found in previous studies that when they
activated Siglec-8 on the surface of
eosinophils, the cells promptly died. Expecting the same suicidal
response in mast cells, the scientists
tested their theory in a new study on human mast cells and mast
cell-containing tissues.
Using mast cells grown in a lab, the researchers used
antibodies to activate Siglec-8.
"We were surprised to see that these cells just sat there
happily in their petri dishes and lived
on," said Bochner, director of the
Division of
Allergy and Clinical Immunology at the Johns Hopkins
University School of Medicine.
With their initial theory disproven, Bochner and his
colleagues suspected that Siglec-8 might be
slowing down other cellular processes based on the protein's
distinctive structure. To investigate what
else Siglec-8 might inhibit, the scientists once again activated
the protein in mast cells with
antibodies. Then, they attempted to trigger an allergic response
from these cells.
Normally, mast cells respond with an outpouring of
histamine, prostaglandins and other
substances that spur allergic reactions in other cells. However,
Bochner and his colleagues found that
cells with activated Siglec-8 released less than half the typical
amount of these substances.
Extending their experiment from cells to whole tissues,
Bochner and his colleagues used
antibodies to activate mast cells' Siglec-8 in small pieces of
human lung saved from autopsies. When
the researchers triggered the cells to release their payloads
— an act that typically causes airways to
sharply constrict — the contractions were about 25 percent
weaker than in lung tissue where the mast
cells' Siglec-8 wasn't activated.
The researchers are still unsure exactly how Siglec-8
inhibits mast cells from releasing their
immune-triggering chemicals. However, follow-up experiments
suggested that activating the protein
keeps calcium from moving efficiently into the cells. Mast cells
need this calcium signal to release
their contents.
Bochner notes that researchers might eventually use these
results, published in the February
Journal of Allergy and Clinical Immunology, to develop a
drug
with this same effect. Such a drug would
have the dual effect of blocking or reducing allergic reactions
by killing eosinophils and preventing
mast cells from releasing their substances.
"Both of these effects could make allergic diseases and
asthma less severe," he said. "It's an
intriguing approach because there are no drugs that specifically
target both these cell types."
Though drugs exist that affect either eosinophils or mast
cells, Bochner says that developing a
single drug that takes aim at both types of cells could be even
more effective than existing therapies
and may also have a reduced risk of side effects. He and his
colleagues are also searching for natural
molecules in the body that activate Siglec-8, which could bring
researchers a step closer to developing
pharmaceuticals that target this protein.
Additional Johns Hopkins researchers who contributed to this
paper are Hidenori Yokoi, Oksoon
H. Choi, Walter Hubbard, Hyun-Sil Lee, Brendan J. Canning, Hyun
H. Lee, Seung-Duk Ryu, Stephan von
Gunten, Carol A. Bickel, Sherry A. Hudson and Donald W.
MacGlashan Jr.
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