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In this edition of the SITNFlash we explore some new findings in the field of asthma research. Studies have found that asthma levels are on the rise in our society, and therefore understanding this condition is more important than ever. Greater understanding translates into more effective treatments and healthier people.
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Breathing New Life into Asthma Research
You may not think of asthma as a killer illness, but each year nearly 500,000 Americans are hospitalized with asthma and more than 4,000 die from asthma attacks. Although for the vast majority of asthmatics the condition will not result in a medical emergency, asthma is a serious health problem in our society --even more so because of its sheer prevalence. It is estimated that asthma affects 4-5% of the U.S. population, and these numbers appear to be on the rise. Modern medicine provides many drugs and treatment options that can help to prevent and control asthma symptoms, but our understanding of this condition is far from complete. Recently, scientists at Harvard Medical School and Children’s Hospital, Boston, discovered an unexpected new member in the gang of asthma instigators. They found that a newly recognized type of immune cell, known as natural-killer T cells (NKT cells), are present in the lungs of asthmatics and that these cells have an important role in triggering the inflammation which leads to asthma symptoms. This finding may explain why current therapies sometimes fail and hopefully lead to more effective treatments for asthma.
What is asthma and what causes it?
Asthma is a state of persistent inflammation of the airways. The inflammation makes the airways very sensitive to irritants like viruses, air pollutants, and allergens (pollen, mold, cockroaches, etc.). When stimulated by these irritants, the airways narrow and secret more mucus. Therefore, less air flows to the lungs resulting in symptoms such as difficulty breathing, coughing, and wheezing. These attacks can resolve spontaneously or subside with medication. Under the microscope, doctors and scientists can see the abnormal presence of immune cells in the lung tissue biopsied from asthmatics. These immune cells (called eosinophils, neutrophils, and lymphocytes) are usually circulating in the blood but are able to infiltrate the lung tissues of individuals with asthma.
The presence of immune cells in lung tissue can explain many asthma symptoms. Immune cells secret proteins called cytokines (pronounced sigh-toe-kines) that not only induce inflammation but also recruit more inflammatory cells to the airway and lungs, thus creating a self-perpetuating loop. Why would immune cells, which are supposed to keep us healthy, cause inflammation? It is thought that the inflammation reaction is a defense mechanism our bodies have evolved to combat foreign invaders. However, in the case of asthma, the immune system overacts, and the cytokines produce intense inflammation resulting in unwanted and dangerous symptoms.
What does the latest research show?
Scientists had previously believed that CD4+ T lymphocytes, specifically a kind called type 2 helper cells (Th2 cells), played the most important role in generating the inflammatory process of asthma. Therefore, companies developed drugs containing corticosteroids, such as Flovent and Azmacort, which target the Th2 cells as well as some other inflammatory cells. Although this treatment brings relief to some asthma sufferers, it does not help all asthmatics. Therefore, it was clear that something else was going on.
In order to learn more about asthma, many scientists rely on mouse models of the condition. Mice experience asthma symptoms upon exposure to certain allergens just like people do. Recently, scientists at Children’s Hospital, Boston noticed that mice bred to lack NKT cells were curiously resistant to asthma. Even when the researchers tried to induce asthma in these mice the mice did not develop asthma. However, when the researchers exposed the mice to an allergen after injecting them with the compatible NKT cells, the mice immediately displayed symptoms of asthma [1]. This was the first indication that NKT cells may be essential for the development of asthma. The researchers went on to show that specific activation of NKT cells was sufficient to produce the core features of asthma even in mice that lacked conventional immune cells, CD4+ T cells [2].
It is important to keep in mind that just because mice get asthma symptoms like humans and are mammals like humans, they are still quite different creatures. To see if these results applied to humans the researchers looked for signs of unusual NKT activity in asthmatics. Specifically, they examined lung specimens from 25 adults: 14 with moderate-to-severe asthma, 6 healthy subjects, and 5 subjects with another respiratory inflammatory disease, sarcoidosis, which is characterized by high levels of CD4+ T cells in the lungs. They found that at least 2/3 of the T cells in the lungs of the asthma patients were NKT cells. In contrast, NKT cells were virtually absent in the lungs of healthy subjects and in patients with sarcoidosis [3]. These findings strengthen the possibility that NKT cells play a direct causative role in generating asthma not only in mice, but in humans as well.
New Directions
The surprising finding that it may be NKT cells and not CD4+ T cells that are to blame for the majority of airway inflammation in asthmatics could change the way that asthma is treated. Corticosteroids, the current mainstay of asthma treatment, target Th2 cells and other inflammatory cells, but they appear to have little effect on NKT cells. Therefore, drugs that specifically eliminate NKT cells, or which reduce their activity, may lead to more effective treatments for asthma. However, NKT cells are also part of our innate immune system and have a crucial role in responses to infections, cancer, and autoimmune diseases. Therefore, the focus will be on developing ways to target NKT cells in the airways and lungs of asthmatics.
--Geng Li, Harvard Medical School
Primary Articles
1. Akbari O et al. Essential role of NKT cells producing IL-4 and IL -13 in the development of allergen-induced airway hyperreactivity. Nat Med. 2003 May: 582-588
2. Meyer EH et al. Glycolipid activation of invariant T cell receptor+ NK T cells is sufficient to induce airway hyperreactivity independent of conventional CD4+ T cells. Proc Natl Acad Sci USA . 2006 Feb 14: 2782-2787
3. Arbari O et al. CD4+ invariant T-cell-receptor+ natural killer T cells in bronchial asthma. N Engl J Med. 2006 Mar 16: 1117-1129
For more information:
Harvard Medical School http://focus.hms.harvard.edu/2006/032406/immunology.shtml
Childrens' Hospital Boston http://www.childrenshospital.org/newsroom/Site1339/mainpageS1339P1sublevel194.html
National Lung Association, Canada http://www.lung.ca/diseases-maladies/asthma-asthme_e.php/
National Institutes of Health http://health.nih.gov/result.asp/56/15
