A group of Israeli researchers has found a mechanism to keep an allergy- and autoimmune disease-causing type of white blood cell from entering the bloodstream. The discovery represents a breakthrough in the understanding of the immune system and suggests a powerful new treatment approach for common conditions such as asthma.

The problematic white blood cells, called eosinophil granulocytes, are part of the immune system that fights infections. However, when eosinophil cells become overactive, they trigger many forms of asthma, gastrointestinal diseases, blood disorders and even cancers.

The study was led by Ariel Munitz of Tel Aviv University’s department of clinical microbiology and immunology at the Sackler School of Medicine, and conducted by graduate students Netali Baruch Morgenstern and Dana Shik.

In healthy people, eosinophils account for less than five percent of the white blood cells circulating in the bloodstream. But in people with an eosinophil disorder, a signaling protein called interleukin 5 (IL-5) triggers a rush of newly produced eosinophils from the bone marrow into the bloodstream. IL-5 is already under clinical investigation as a new target for asthma medications.

Tug-of-war between IL-5 and PIR-A

Analyzing the bone marrow of mice, the researchers found that the abnormal release of eosinophils caused by IL-5 is actually part of a microscopic tug of war regulating the lifecycle of these cells. IL-5’s stronger “opponent,” paired immunoglobulin-like receptor A (PIR-A), programs eosinophils to die.

But here’s the catch. PIR-A’s “death orders” normally are inhibited by the action of another receptor, PIR-B. In order for PIR-A to do its job of keeping eosinophil numbers down to normal levels, PIR-B must be neutralized.

“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.”

As expected, the researchers found that asthmatic mice without PIR-B in their bodies had very little expansion of eosinophils into their blood and lungs and therefore less asthmatic inflammation in their lungs compared with normal mice. Unhindered by PIR-B, PIR-A appeared to keep eosinophils from reaching harmful levels in the rodents’ bodies.

Because human eosinophils also express PIR-like molecules, there is good reason to believe the same mechanism is at play in people. Now, the researchers are working to identify other mechanisms in which PIR-B inhibits cell death.

Two possible treatment directions

In addition to advancing knowledge of eosinophils — a basic and important cell type — the Israeli researchers’ work opens up two new avenues for treating eosinophilic disorders.

Instead of lowering IL-5 levels to try to reduce eosinophil expansion, scientists can now try to enhance PIR-A’s natural ability to kill eosinophils. Another approach might be to weaken PIR-B so that it cannot as effectively inhibit PIR-A.

ISRAEL21c previously wrote about Munitz’s team discovering a new pathway for treating colorectal cancer and pulmonary fibrosis. This study looked at macrophages, a type of white blood cell that can worsen certain medical conditions if it is exposed to the wrong stimulus.

The current study on eosinophil granulocytes was published online in Nature Immunology  in November. Carried out in collaboration with the division of allergy and immunology at the Cincinnati Children’s Hospital Medical Center, the research was funded in part by the United States-Israel Binational Science Foundation, the Israel Science Foundation, the Israel Cancer Research Fund and the Fritz Thyssen Stiftung.