Research at Tel Aviv University reveals a new mechanism that activates cells responsible for chronic inflammatory diseases such as allergies and asthma

The discovery has a decisive impact on the understanding of the biological processes underlying the differentiation of white blood cells in general, and on the treatment of chronic inflammatory diseases in particular. The research is published today in the prestigious journal Nature Immunology

A new study by Dr. Ariel Munitz from the Faculty of Medicine at Tel Aviv University reveals the biological mechanism behind the differentiation of white blood cells called eosinophils - cells responsible for many of the symptoms of chronic inflammatory diseases such as asthma, allergies, inflammatory bowel diseases and even cancer. The research is published today (10.11.13) in the important journal Nature Immunology.

"Eosinophils are cells that under normal conditions develop in the bone marrow, enter the bloodstream and from there flow to the mucous tissues," explains Dr. Munitz. "In healthy people, the percentage of eosinophils in the blood is relatively low, approximately 2-5% of all white cells, on the other hand, in patients with allergic diseases, and especially in patients with asthma, the concentration of eosinophils increases significantly. In asthma, the excess eosinophils differentiate in the bone marrow, enter the bloodstream and eventually reach the lungs, where they release a series of toxic molecules that directly or indirectly cause tissue damage, shortness of breath, mucus secretion and so on. In fact, eosinophils are responsible for a significant part of the known symptoms of asthma."

For this reason, explains Dr. Munitz, eosinophils are used today as a pharmacological target for the treatment of asthma patients. There are several experimental drugs that try to suppress their differentiation in the bone marrow or their migration from the bone marrow to the lungs - most of them by suppressing a protein called IL-5, which is known to stimulate the production of eosinophils."

A complete biological mechanism

Until now, the protein IL-5 was the only factor that was known to science as a factor influencing the differentiation of eosinophils. In their new study, Dr. Munitz, along with doctoral students Natali Morgenstern Ben Baruch and Dana Schick, identified two additional proteins that play a crucial role in the differentiation of eosinophils.

"We discovered that a protein called PIR-B controls the production of eosinophils in the bone marrow. This is a well-known protein, which is expressed in additional white blood cells - but to date no one has linked it to the production of eosinophils, or even to the differentiation of white blood cells. We began to investigate the PIR-B protein after we recognized that it is expressed at abnormal levels in eosinophil cells, and especially in eosinophils that we took from asthmatic mice. When we tried to grow eosinophils in the laboratory from the bone marrow of a healthy mouse and the bone marrow of a mouse without PIR-B, we discovered that all the eosinophils we tried to grow in cultures without this protein died within a week, and did not differentiate into mature cells. In a second step, we discovered that the PIR-B protein actually inhibits the action of another protein from the same family: PIR-A, which transmits to eosinophils the instruction to die. In fact, we uncovered an entire biological mechanism, unique to this cell: the PIR-B protein inhibits the lethal action of the PIR-A protein depending on the concentration of the IL-5 protein, which encourages the differentiation of eosinophils. Like in a tug of war, each protein pulls in a different direction until a balance is created."

The new research has a decisive impact on the understanding of the biological processes underlying the differentiation of white blood cells in general, and on the treatment of chronic inflammatory diseases in particular. "Each of the proteins we identified - both the protein that mediates the killing of eosinophils and the protein that inhibits the activity of the killer protein - can be used as a new target for the treatment of asthma, and as a potential treatment for any disease that involves the recruitment and activation of eosinophils. When we induced asthma in laboratory mice lacking the inhibitory protein PIR-B, we saw that the eosinophils did not reach the lungs, and the inflammation characteristic of asthma subsided significantly."

The study, which lasted 4 years and was conducted in collaboration with the Department of Allergy and Immunology at the Children's Hospital in Cincinnati, Ohio, was partially funded by the Binational Science Foundation (BSF), the National Science Foundation (ISF), the Israel Cancer Research Fund (ICRF), a grant from the European Union and research grants from the NIH.