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NIAID Researchers Identify Potential Drug Target for Allergies

Protein Variant Promotes Allergic Response in Cell Culture Experiments

NIAID scientists have shown that a newly identified molecule helps promote the release of chemicals that cause allergic reactions. Unraveling the role of this molecule in immune cell function may help researchers devise new treatments for allergy and asthma. The scientists report their findings online ahead of the May 23, 2013, print issue of Immunity.

Background

An allergic reaction occurs when activated mast cells degranulate, releasing inflammatory chemicals such as histamine.

An allergic reaction occurs when activated mast cells degranulate, releasing inflammatory chemicals such as histamine.
Credit: View credit information.

Mast cells are specialized immune cells that contain small granules packed with inflammatory chemicals. When an allergy-prone person encounters an allergen, the immune system produces immunoglobulin E (IgE) antibodies, which attach to the surface of mast cells. When the person is exposed to the allergen a second time, the allergen interacts with IgE on the mast cell surface, triggering the cells’ release of the chemicals, a process called degranulation. The chemicals, which include histamine, cause allergy symptoms such as watery eyes, runny nose, and itching.

Mast cells recognize IgE through special receptors on their surface. Each IgE receptor comprises three different types of proteins—the alpha, beta, and gamma chains. During the 1990s, scientists found that the gene that encodes the IgE receptor beta chain may be associated with the development of allergies and asthma.

Researchers led by Glenn Cruse, Ph.D., of NIAID’s Laboratory of Allergic Diseases recently identified a naturally occurring, shortened variant of the IgE receptor beta chain. Unlike the full-length beta chain, which binds to the alpha chain on the surface of mast cells, this variant stays within the cell, where the scientists suspected it might participate in the processes that lead to allergic inflammation.

Results of Study

In a series of experiments in laboratory-grown human mast cells, NIAID researchers found that the shortened IgE receptor beta chain plays a unique role in stimulating degranulation. When mast cells are activated, levels of calcium—an important cell-signaling molecule—rise. This increase promotes the signaling events within the cells that lead to degranulation. The scientists found that the shortened variant of the beta chain recognizes and binds to calcium-sensing proteins. After this binding occurs, the shortened variant moves to regions within the cell where microtubules—tiny components of cells that are involved in the movement of granules—form. There, the protein participates in microtubule formation and degranulation, helping to trigger the chemical release that leads to allergy symptoms.

Significance

A human mast cell with the shortened beta chain variant in green, a protein constituent of microtubules in red, and the cell nucleus in blue.

A human mast cell with the shortened beta chain variant in green, a protein constituent of microtubules in red, and the cell nucleus in blue.
Credit: NIAID

Understanding the events involved in mast cell activation and degranulation can help researchers identify potential targets for the treatment of allergy and asthma. Drugs that block the function of molecules such as the protein described in this study could help prevent or control allergic reactions. However, the researchers emphasize that more work is needed to better understand the function of the shortened IgE receptor beta chain.

Next Steps

The NIAID scientists are developing new cell-culture and animal models to further study the function of the beta chain variant in mast cells. In particular, they hope to identify the parts of the protein that are important for signaling. The researchers also plan to examine the effect on mast cell function of variations and mutations in the gene encoding the beta chain.

Reference

Cruse G, Beaven MA, Ashmole A, Bradding P, Gilfillan AM, Metcalfe D. A truncated splice variant of the FcεRIβ receptor subunit is critical for microtubule formation and degranulation in mast cells. Immunity DOI: 10.1016/j.immuni.2013.04.007, (2013).

Immune System Glossary

Laboratory of Allergic Diseases, Mast Cell Biology Section

Last Updated April 30, 2013

Last Reviewed April 30, 2013