Asthma

The Problem

The incidence of asthma in the United States (as well as in many other developed countries) has reached epidemic proportions. In the last two decades, the number of sufferers in the U. S. has doubled to more than 14 million people.

The Mechanism

• histamine and
• leukotrienes

• cause the smooth muscle cells of the bronchi to contract narrowing the lumen of the bronchi. This is the early phase.
• attract an accumulation of inflammatory cells — especially eosinophils — and the production of mucus. This is the late phase. With repeated attacks, the lining of the bronchi becomes damaged.

Why do some people develop asthma from exposure to agents that are harmless to others?

For reasons that are not yet understood, some people have a predisposition to respond to antigens by making antibodies of the IgE class. The trait tends to run in families suggesting a genetic component. These people are said to suffer from atopy.

The T helper cells of atopic people are largely of the Th2 type rather that Th1.

And mice whose genes for a transcription factor (called "T-bet") used to make Th1 cells have been knocked out

• make fewer Th1 and more Th2 cells and
• suffer the lung changes typical of human asthma even though not exposed to any known allergen.

• help B cells make IgE antibodies by synthesizing interleukin 4 (IL-4) and interleukin 13 (IL-13), which promote class switching.
• release interleukin 5 (IL-5) which attracts eosinophils and other inflammatory cells to the site, producing the late phase of the response.

Why is asthma a disease of developed countries?

No one knows for certain.

It is certainly not a matter of air pollution. Air pollution can trigger attacks of asthma, but some regions with heavily-polluted air have a much lower incidence of asthma than regions with relatively clean air.

One intriguing possibility: sanitation and widespread childhood immunization may enable children to avoid the infections — especially viral — that stimulate the immune system to respond with Th1 helper cells rather than Th2 cells. Children in Europe that give positive DTH responses to tuberculin (a response mediated by Th1 cells) have lower rates of asthma than children who are negative in the tuberculin test. European children growing up on farms where they are exposed to high levels of bacteria and fungi associated with farm animals have a lower incidence of asthma and atopy than their suburban peers.

But children in tropical, undeveloped countries, who are often infected with parasitic worms, have high levels of Th2 cells and IgE but a very low incidence of asthma. Perhaps, then, a variety of chronic infections in childhood activate mechanisms (e.g., production of regulatory T cells) that suppress all inflammatory immune responses both Th1- and Th2-mediated.

Treatments

Beta-adrenergic agonists

• These drugs (albuterol is a popular example) mimic the action of adrenaline.
• They relax the smooth muscle of the bronchi.
• They may be inhaled or given by mouth.
• While useful in the early phase of an attack, they provide no protection against the longterm damage produced during the late phase.

Corticosteroids

• These drugs reduce the inflammation of the late phase of the response.
• They may be given in an inhaler (e.g., beclomethasone) or by mouth (e.g., prednisone)

Cromolyn sodium

• inhibits exocytosis of mast cells thus blocking the release of histamine and leukotrienes.
• It is used mainly to prevent attacks (e.g., triggered by exercise) and is of no use in the early phase of an ongoing attack.

Leukotriene inhibitors

• Zileuton (Zyflo®) blocks leukotriene synthesis by inhibiting the action of 5-lipoxygenase.
• Montelukast (Singulair®) blocks the leukotriene receptors on the surface of
  • smooth muscle cells
  • eosinophils

Possible future treatments still under investigation

• Anti-IgE antibodies. These interfere with the binding of IgE to mast cells. Omalizumab (Xolair®), a humanized monoclonal antibody produced by recombinant DNA technology, has been approved for use against allergic asthma (but carrying a "black-box" warning of the slight risk of its precipitating an anaphylactic reaction).
• Drugs that bind to IL-13 keeping it from promoting IgE synthesis.
• Treatments that stimulate the production of Th1 cells by the immune system. Injections of a harmless mycobacterium (a relative of the TB bacillus) might do the trick. Th1 cells secrete interferon-gamma which is a powerful inhibitor of Th2 cells. [Discussion with graphic]

Some of these treatments are already in clinical trials. [Discussion of how new drugs are tested]