|Abnormal Immune Cells May Cause Unprovoked Anaphylaxis
Two new clinical reports shed light on why some people suffer
from recurrent episodes of idiopathic anaphylaxis — a potentially
life-threatening condition of unknown cause characterized by a
drop in blood pressure, fainting episodes, difficulty in breathing,
In some of these individuals, researchers have found mast cells
(a type of immune cell involved in allergic reactions) that have
a mutated cell surface receptor that disturbs normal processes
within the cell. Scientists supported by the National Institute
of Allergy and Infectious Diseases (NIAID), part of the National
Institutes of Health (NIH), say the association of this mutation
with unprovoked anaphylaxis is striking. The hope is that these
individuals may respond to inhibitors targeting the mutated cell
While some people suffer anaphylaxis as part of a serious allergic
reaction, in two out of three people, anaphylaxis has no known
cause and thus the anaphylactic reaction is called idiopathic.
Anaphylaxis occurs when mast cells release large quantities of
chemicals (histamines, prostaglandins and leukotrienes) that cause
blood vessels to leak, bronchial tissues to swell and blood pressure
to drop. Resulting conditions such as shock and unconsciousness
usually resolve in most people treated with epinephrine (adrenaline)
and first aid measures. In rare cases, however, death may occur.
Abnormally low blood pressure and fainting episodes are also features
of mastocytosis—a disease in which people have an excessive number
of mast cells. Several years ago, Dean Metcalfe, M.D., chief of
the Laboratory of Allergic Diseases at NIAID, Cem Akin, M.D., Ph.D.,
and their NIAID colleagues decided to find out whether idiopathic
anaphylaxis might have a genetic trigger related to that seen in
mastocytosis. It is known that systemic mastocytosis in adults
often results from a mutation in the Kit receptor found on the
surface of mast cells, a discovery first made by Dr. Metcalfe’s
team in 1995.
The mutation causes an abnormal growth of mast cells, as is observed
in bone marrow biopsies of patients with mastocytosis. So the NIAID
team asked, if the Kit mutation could make mast cells grow and
cause mastocytosis, and this was associated with anaphylactic reactions,
could the same mutation predispose mast cells to release chemicals
responsible for idiopathic anaphylaxis?
In a two-year study conducted at the NIH Clinical Center, the
researchers examined 48 patients diagnosed with mastocytosis with
or without associated anaphylaxis, 12 patients with idiopathic
anaphylaxis, and 12 patients with neither disease. Within the group
of 12 patients who had idiopathic anaphylaxis, five were found
with evidence of a disorder in a line of mast cells (clonal mast
cell disorder). The researchers looked for evidence of a Kit mutation
in three patients by analyzing bone marrow samples, and all three
samples yielded a positive result. The findings demonstrate that
some patients with idiopathic anaphylaxis have an aberrant population
of mast cells with mutated Kit.
"We believe the mutation may be predisposing people to idiopathic
anaphylaxis," says Dr. Metcalfe. "Our findings suggest
that in patients with idiopathic anaphylaxis as well as in people
with severe allergies, we should look for critical genetic mutations
that may change the way a mast cell reacts."
Dr. Metcalfe and his NIAID colleagues report their findings in
two journals. The study that appears in an early online edition
in Blood describes the presence of an abnormal mast cell
population in a subset of patients with idiopathic anaphylaxis.
The findings about the mechanism leading to mass cell activation
by Kit and the IgE receptor responsible for allergic reactions
appear online in Cellular Signalling.
According to the NIAID team, both Kit and the IgE receptor responsible
for allergic reactions activate mast cells via a common interior
protein of mast cells. They also found that the mutated Kit markedly
elevates the activity of that protein, which results in increased
The scientists are now looking to see if artificial mast cells
with mutated Kit behave or release chemicals in a manner different
from normal mast cells, and also if they respond to inhibitors
News releases, fact sheets and other NIAID-related materials are
available on the NIAID Web site at http://www.niaid.nih.gov.
NIAID is a component of the National Institutes of Health. NIAID
supports basic and applied research to prevent, diagnose and treat
infectious diseases such as HIV/AIDS and other sexually transmitted
infections, influenza, tuberculosis, malaria and illness from potential
agents of bioterrorism. NIAID also supports research on basic immunology,
transplantation and immune-related disorders, including autoimmune
diseases, asthma and allergies.
The National Institutes of Health (NIH) — The Nation's
Medical Research Agency — includes 27 Institutes and
Centers and is a component of the U.S. Department of Health and
Human Services. It is the primary federal agency for conducting
and supporting basic, clinical and translational medical research,
and it investigates the causes, treatments, and cures for both
common and rare diseases. For more information about NIH and
its programs, visit www.nih.gov.
C Akin et al. Demonstration of an aberrant mast cell population
with clonal markers in a subset of patients with recurrent anaphylaxis. Blood DOI:
S Iwaki et al. KIT and FceRI-induced differential phosphorylation
of the transmembrane adaptor molecule NTAL/LAB/LAT2 allows flexibility
in its scaffolding function in mast cells. Cell Signal DOI: