Students at Tel Aviv University 370.
(photo credit: Danielle Ziri)
Tel Aviv University researchers have found a way to put the brakes on white
blood cells and prevent them from going wild and overactive, a condition that
can lead to allergies and autoimmune diseases.
The research has just been published online in the Nature Immunology journal and was funded by the
US-Israel Binational Science Foundation, the Israel Science Foundation, the
Israel Cancer Research Fund and the Fritz Thyssen Foundation.
Munitz of TAU’s department of clinical microbiology and immunology at the
Sackler School of Medicine, along with graduate students Netali
Baruch-Morgenstern and Dana Shik, have found a mechanism that pushes eosinophils
(a type of white blood cell) to die before they get into the blood and wreak
The discovery, they say, is a “breakthrough in science’s
understanding of the immune system and suggests powerful new treatments for
eosinophilic diseases such as asthma.”
The research took four years to
conduct and was carried out in cooperation with the allergy and immunology
department of the Children’s Hospital in Cincinnati, Ohio.
system has a double role. While its prime task is to fight infections, it can
also become overactive, leading to medical problems such as allergies and
For example, the part of the immune system
responsible for resisting parasites acts by releasing white blood cells called
eosinophil granulocytes into the blood. But elevated eosinophil levels are also
responsible for allergic reactions, including most forms of asthma,
gastrointestinal diseases, blood disorders and cancers.
an important and powerful pathway that works to kill eosinophils,” said
“The fundamental knowledge we have gained may one day yield even
bigger results and therapies.”
The level of eosinophils in the blood is
relatively low in healthy people, accounting for just 2-5% of white blood cells
in circulation. But in eosinophilic disorders, a signaling protein called
interleukin 5 (IL-5) triggers a rush of eosinophils from the bone marrow into
the blood, where they are transported to various organs.
bone marrow of mice, the researchers found that the expansion of eosinophils
caused by IL-5 is actually part of a broader mechanism that regulates the life
cycle of the cells.
While IL-5 commands eosinophils to expand and enter
the bloodstream, a cell receptor called paired immunoglobulin-like receptor A,
or PIR-A, commands eosinophils to die. So eosinophils are in a constant “tug of
war” between survival signals delivered by IL-5 and death orders given by
Although the death order by PIR-A is dominant, it is never
executed. Eosinophils express another receptor, called PIR-B, which closely
resembles PIR-A and inhibits its actions. For PIR-A to carry out its death order
to the cell, PIR-B must be shut down.
“PIR-A is always inhibited by PIR-B
from the very early stages of eosinophil development,” said Munitz. “We had to
remove the expression of PIR-B from the cells to see PIR-A’s powerful
After identifying the mechanism in cell culture systems, the
researchers verified that it also operates in mice. As expected, they found that
asthmatic mice without PIRB in their bodies had very little expansion of
eosinophils into their blood and lungs and therefore less asthmatic inflammation
in their lungs than normal mice. Unhindered by PIR-B, PIR-A appeared to keep
eosinophils from reaching harmful levels in their bodies. Because human
eosinophils also express PIR-like molecules, there is good reason to believe the
same mechanism works in people.
In addition to advancing knowledge of
eosinophils – a basic and important cell type – the researchers’ work opens up
two new avenues for treating eosinophilic disorders: either targeting PIR-A to
enhance its ability to kill eosinophils, or weakening PIR-B so that it inhibits