Key Molecule in Severe Chronic Allergy Identified

NIAID-supported scientists at Johns Hopkins Asthma and Allergy Center have identified and purified a key immune system protein linked to severe allergies. Their discovery could lead to new tests to predict which people are at high risk for severe allergic reactions such as life-threatening episodes of asthma.

As reported August 4, 1995, in Science, a protein called histamine-releasing factor (HRF) appears to determine the severity and duration of an allergic response.

"Now that the molecule is identified," comments Marshall Plaut, M.D., chief of NIAID's Allergic Mechanisms Section, "it may be possible to develop antibodies and other reagents that will determine how HRF works and how HRF stimulates severe allergic reactions and asthma. Eventually, this discovery may lead to new ways to treat these diseases."

HRF is one of many immune system molecules called cytokines that trigger allergic reactions. These cytokines prod white blood cells called basophils into releasing histamine and other mediators of symptoms of asthma and allergic diseases. Histamine, in turn, causes the changes in the respiratory system that make breathing difficult.

Histamine is released immediately after a person is exposed to an allergy-causing protein. The allergic reaction then stops. But in about half of all people with allergies, it recurs hours later because of the presence of HRF and other cytokines. This recurrence, called the late-phase reaction, is similar to serious chronic allergy and asthma.

Unlike other cytokines, HRF stimulates basophils to release histamine only when a special type of antibody, a disease-fighting protein called IgE, is attached to those cells. In addition, not all types of IgE cooperate with HRF to cause histamine release.

"Now that we know the structure of a cytokine-HRF--that depends on IgE, we can develop tests to see if a particular person's IgE is sensitive to HRF," says Lawrence M. Lichtenstein, M.D., Ph.D., professor of medicine and director of the Center. He and Susan M. MacDonald, M.D., associate professor of medicine at Hopkins, are the principal authors of the paper.

Although the HRF molecule was first described as a likely trigger of allergic and asthmatic inflammation about ten years ago, until now, this molecule has been extremely difficult to purify or identify.

To study the role of HRF in histamine release, the investigators coated basophils with either IgE+, antibodies that trigger severe allergies in the presence of HRF, or with IgE-, antibodies that do not. When the researchers added HRF to the basophils, histamine was released only when IgE+ was present.

The Hopkins team recovered HRF from several types of immune system cells and fluid including B and T cells, mononuclear cells, and the culture fluid of macrophages--as well as from fibroblasts, cells that develop into the bones and tissues that frame the body and its organs.

The identification and purification of HRF offers hope that new diagnostic tests and novel therapies that block the molecule can be designed to help those who suffer most from asthma and severe allergic diseases.