Binational team of researchers from Israel and US find way to slow down white blood cells

Overactive white blood cells can lead to allergies and autoimmune diseases

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.

Dr. Ariel 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 havoc.

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.

The immune 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 autoimmune diseases.

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.

“We’ve discovered an important and powerful pathway that works to kill eosinophils,” said Munitz.

“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.

Analyzing the 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 PIR-A.

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 effects.”

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 PIR-A less.

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Related publication:

Paired immunoglobulin-like receptor A is an intrinsic, self-limiting suppressor of IL-5–induced eosinophil development Netali Ben Baruch-Morgenstern, Dana Shik,  Itay Moshkovits, Michal Itan,  Danielle Karo-Atar,  Carine Bouffi,  Patricia C Fulkerson,  Diana Rashkovan,  Steffen Jung,  Marc E Rothenberg,  Ariel Munitz, Nature Immunology volume 15, pages 36–44 (2014)

https://www.nature.com/articles/ni.2757

(Published: 10 November 2013)