|Protein Suppresses Allergic Response in Mice
Protein May Play Role in Many Diseases
A protein in mice known as RGS13 suppresses allergic reactions,
including the severe, life-threatening allergic reaction known
as anaphylaxis, according to scientists at the National Institute
of Allergy and Infectious Diseases (NIAID), part of the National
Institutes of Health (NIH). Because RGS13 is also a protein found
in humans and is expressed in only a limited number of cells — including
the immune system’s mast cells that are central to allergic
reactions — scientists believe the protein may be an attractive
target for developing new drugs to treat and prevent certain allergic
reactions, including anaphylaxis.
"We still do not know what triggers the allergic or anaphylactic
reaction in some people," says NIAID Director Anthony S.
Fauci, M.D. "These findings open up important research avenues,
such as examining the role of RGS13 protein in humans to determine
if its deficiency or abnormal function triggers the mast cells
to release chemicals that cause allergic diseases."
The research, led by Kirk M. Druey, M.D., senior investigator,
at the Laboratory of Allergic Diseases at NIAID, is described in
a report online in Nature Immunology.
RGS13 is one of a large group of regulator of G protein signaling
(RGS) proteins that act as traffic lights for signaling networks
within cells. Though the biochemical actions of most RGS proteins
in laboratory tests are known, their physiological functions in
the body are still a mystery. Therefore, the current findings may
have broader implications for many different biological processes,
such as metabolism, cancer progression, cardiac function and others.
Mast cells serve an important role in normal immune function,
but little is known about what triggers these cells to sometimes
become overactive and cause allergic reactions. The severity of
an allergic reaction depends on the quantity of chemicals (histamines,
prostaglandins and leukotrienes) released by mast cells. Serious,
quick-onset allergic reactions affecting multiple organs of the
body can lead to anaphylaxis, which is characterized by a drop
in blood pressure, fainting episodes, difficulty in breathing,
and sometimes death.
RGS13 is known to inhibit cellular responses induced by G-protein-coupled
receptors, which are the most abundant cell surface receptors in
the body. It is also known that these receptors are the targets
of approximately 60 percent of therapeutic drugs for various diseases.
Since RGS13 is expressed in mast cells, Dr. Druey and his NIAID
colleagues decided to explore the role of RGS13 in mouse models
of anaphylaxis. Through genetic engineering, they made a group
of mice deficient in the RGS13 gene. Normal mice served as the
First, the NIAID team compared localized anaphylactic reactions
in the two groups. They injected an allergen, IgE antibody and
a blue dye under the skin of the mice, similar to the allergy skin
test done by physicians. The results showed that RGS13-deficient
mice had a larger and more intense blue reaction than normal mice,
indicating that their blood vessels leaked more.
To test for systemic anaphylaxis, they injected the allergen,
IgE antibody and a blue dye directly into the veins of the mice.
The organs of RGS13-deficient mice showed an anaphylactic response
that was twice as large as that of the normal mice. In both cases,
the results indicate that RGS13 suppresses the anaphylactic response
in mice, whereas RGS13 deficiency and abnormal RGS13 expression
and function contribute to increased mast cell activity, which
occurs during an allergic response, including anaphylaxis.
According to Dr. Druey, the study is also important because for
the first time, researchers have shown that RGS13 inhibits the
activity of PI3 kinase, an enzyme involved in many biological processes,
including those involved in cancer and diabetes. Therefore, the
research has implications for numerous other diseases and medical
conditions in addition to allergies.
Next, the NIAID team will analyze the expression of RGS13 in human
mast cells in healthy individuals and in people with allergy or
anaphylaxis, search for specific gene mutations in these populations,
and determine whether abnormal expression or function of RGS13
correlates with specific allergic diseases.
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.
G Bansal et al. Suppression of immunoglobulin E–mediated
allergic responses by regulator of G protein signaling 13. Nature
Immunology DOI: 10.1038/ni1533 (2007).