MAST CELLS: MASTERMINDS OF ALLERGIC DISEASE

SEATTLE—Of the many cells that cause lower airway inflammation, perhaps none is more important than the mast cell. When activated, mast cells are a principal cell initiating asthma exacerbations, stressed Dean D. Metcalfe, MD, who reviewed their role in the development of asthma and allergic diseases at the annual meeting of the American College of Allergy, Asthma, and Immunology.[1]

Mast cells originate from pluripotential CD34+, CD13+, and CD117+ cells. The mast cells enter the bloodstream, migrate throughout the body, and mature. They frequently locate at perivascular sites in tissues, such as the lungs, where they interact with the external environment.

Mast cells become activated when surface receptor-bound antigen-specific immunoglobulin E (IgE) encounters an antigen that the IgE recognizes. This triggers mast-cell degranulation, leading to the rapid release of inflammatory mediators, such as histamine, proteoglycans, and cytokines. Mast-cell activation also stimulates the arrival of other inflammatory cells—a critical step in local inflammation, Dr. Metcalfe pointed out.

Smooth muscle contraction with subsequent bronchoconstriction is a potential result of mast-cell activation in the lungs, as are lower airway inflammation, increased mucus production, and other features of allergic disease. Once this process has begun, further mast-cell activation and mediator release may be triggered by anaphylatoxins generated during the inflammatory response and by heterotypic aggregation with activated T lymphocytes. With continued antigen exposure, the inflammatory response perpetuates itself, and lower airway inflammation becomes chronic.

Therapy directed at mast cells would theoretically be an ideal way to combat asthma and allergic diseases. But such treatments are not available. “There has never been a drug that can be taken systemically—meaning a pill—that selectively blocks mast-cell activation without causing toxic effects,” said Dr. Metcalfe, Chief of the Laboratory of Allergic Diseases at the National Institute of Allergy and Infectious Diseases in Bethesda, Maryland. If such a drug were available, it “would probably be excellent for the treatment of allergic diseases,” he added.

Thus, treatment must be directed at the multitude of different mediators that are activated by mast cells. As a result, no single medication can adequately treat lower airway inflammation, Dr. Metcalfe told RESPIRATORY REVIEWS. “Most only block part of the inflammatory reaction. That is why combination therapy is reasonable for the treatment of allergic diseases.”

Combination therapy often includes corticosteroids, which are effective because they blunt the effects of multiple mediators. Future studies will focus on identifying the best combination therapies for allergic diseases. Researchers have tried, although without much success, to create a class of drugs that prevents mast-cell activation. Cromolyn sodium is thought to prevent mast-cell activation. Because it is inhaled, however, it can only have that effect in the parts of the lung that it reaches, Dr. Metcalfe reported.

--Timothy Begany