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|Asthma and Other Allergies Tied to Absence of Specialized Cells|
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When it comes to allergies, both the problem and the solution are found within us. Our immune systems respond to foreign substances with an arsenal of cells. Some are programmed to "remember" invaders they've encountered in the past. Normally, anything previously identified as harmless is allowed to pass. Sometimes, however, the immune response goes awry, triggering an allergic reaction.
Now, researchers at NYU School of Medicine have zeroed in on a class of custom-made immune cells that block allergic reactions. These regulatory T cells are manufactured according to instructions from a gene called Foxp3 whenever we eat or inhale a potential allergen for the first time, ensuring that the next time we encounter that substance, we will not mount an allergic response.
"We don't become allergic to lots of things-we eat all kinds of things, we breathe all kinds of things, and what prevents us from developing allergies is that we make regulatory T cells, which specifically recognize this allergen," says Maria A. Curotto de Lafaille, Ph.D., Associate Research Scientist at NYU Langone Medical Center. "Every time we don't react to something or don't become allergic, it's not because nothing is happening," Dr. de Lafaille explains. "It's because something very important is happening: We're making these cells,"
Mucosal tissue, which lines both the respiratory and digestive tracts, has long been known as an effective barrier against allergens, which are always protein molecules. The NYU research shows that Foxp3-directed regulatory T cells (Treg) are produced in the mucosal tissue and remain there to prevent allergic reactions. New ones are tailor-made every time an unknown protein is inhaled or ingested. The inability to make Treg cells results in high susceptibility to becoming allergic.
The NYU researchers induced allergic reactions in mice with a Foxp3 mutation that prevented formation of Treg cells. Exposure to the same allergen-in this case egg protein-did not elicit an allergic response in mice that were able to make Treg cells. The findings are reported in the July 18, 2008, issue of the journal Immunity.
The formation of Foxp3-positive Treg cells occurs in response to any potential allergen, so the findings are applicable to a broad range of allergic reactions and autoimmune diseases, says Dr. de Lafaille. When people suffer from allergies, including life-threatening ones such as asthma, something goes wrong in the process by which Foxp3 signals Treg cell formation. The problem is not necessarily a mutation in the Foxp3 gene, which is known to cause severe autoimmune disease. Rather, something occurs, or fails to occur, in the lungs or the gut that interferes with the production or activity of allergen-specific Treg cells.
The NYU researchers also determined that Treg cells control damage from long-term inflammation. They found high concentrations of Treg cells in inflamed lung tissue of mice without the Foxp3 defect. "The question arose about what these cells are doing in the tissue-are they beneficial or not?" Dr. de Lafaille says. It turns out that even though the Treg cells did not prevent inflammation in an ongoing allergic reaction, they kept it under control, ensuring it did not worsen or spread to other areas of the body. "We think that over time these regulatory T cells become more important than the inflammatory cells and end up completely shutting off the inflammation. But it's not overnight and it's not black and white," Dr. de Lafaille emphasizes.
This finding provides a key to one of the most serious consequences of asthma. In addition to breathing problems during an acute attack, people with asthma have chronic inflammation, which can permanently damage their airways. If a means could be found to increase the number of Treg cells in inflamed tissue, this might be prevented. Allergic asthma, the most common and best-understood type, affects more than 10 million people in the US, many of them children. Acute asthma attacks are responsible for nearly 4000 deaths in the United States each year.
Dr. Yi Ding, Dr. de Lafaille, and other members of Dr. Juan Lafaille's laboratory have been investigating ways to grow allergen-specific Treg cells in the lab and inject them into people who cannot make their own. The group published a paper in Nature Medicine in February 2008 describing a method of making the cells. "The big challenge is how to isolate the cells that will recognize the right allergens that the person is allergic to," Dr. de Lafaille says. Another approach is to stimulate the body to manufacture the cells itself, an area of ongoing research.
This work represents an important step in understanding the genetic and cellular mechanisms underlying the allergic response, which may lead to more effective therapies. Current treatment is aimed at suppressing symptoms and reducing inflammation after an allergic reaction has already occurred. Having identified the cell type that must be present to prevent allergies, Dr. de Lafaille and her colleagues are now looking for the glitch that blocks formation of those cells.
The study published in the journal Immunity was supported by grants from the National Institutes of Health, the National Multiple Sclerosis Society, and the Sandler Foundation. The co-authors of the study include: Nino Kutchukhidze and Shiqian Shen, former postdoctoral students in pathology, Yi Ding, a graduate student in pathology, and Herman Yee, M.D., Ph.D., associate professor of pathology, and Juan J. Lafaille, Ph.D., associate professor of pathology and Medicine at NYU Langone Medical Center.
About Autoimmune Disease
An autoimmune disorder is a condition that occurs when the immune system mistakenly attacks and destroys healthy body tissue. Autoimmune diseases can affect virtually every site in the body, including the endocrine system, connective tissue, gastrointestinal tract, heart, skin, and kidneys. At least 15 diseases are known to be the direct result of an autoimmune response, while circumstantial evidence implicates >80 conditions with autoimmunity There are more than 80 different types of autoimmune disorders.
Autoimmune diseases are currently ranked as the third biggest disease category in the US behind heart disease and cancer. An estimated 3% of the population in the United States is affected by a tissue-specific or systemic autoimmune disorder. In many other parts of the world they rank as the biggest disease category.
Normally the immune system's army of white blood cells helps protect the body from harmful substances, called antigens. Examples of antigens include bacteria, viruses, toxins, cancer cells, and foreign blood or tissues from another person or species. The immune system produces antibodies that destroy these harmful substances.
But in patients with an autoimmune disorder, the immune system can't tell the difference between healthy body tissue and antigens. The result is an immune response that destroys normal body tissues. The response is a hypersensitivity reaction similar to allergies, where the immune system reacts to a substance that it normally would ignore. In allergies, the immune system reacts to an external substance that would normally be harmless. With autoimmune disorders, the immune system reacts to normal body tissues.An autoimmune disorder may affect one or more organ or tissue types. Organs and tissues commonly affected by autoimmune disorders include:
Factors which predispose to the development of autoimmunity include genetic factors, age of the individual and environmental factors such as stress and infectious agents.
Asthma occurs when the main air passages of your lungs, the bronchial tubes, become inflamed. The muscles of the bronchial walls tighten, and cells in the lungs produce extra mucus further narrowing your airways. This can cause minor wheezing to severe difficulty in breathing. In some cases, your breathing may be so labored that an asthma attack becomes life-threatening.
Asthma is a chronic but treatable condition. You can manage your condition much like someone manages diabetes or heart disease. You and your doctor can work together to control asthma, reduce the severity and frequency of attacks and help maintain a normal, active life.
Asthma signs and symptoms can range from mild to severe. You may have only occasional asthma episodes with mild, short-lived symptoms such as wheezing. In between episodes you may feel normal and have no difficulty breathing. Some people with asthma have chronic coughing and wheezing punctuated by severe asthma attacks.Most asthma attacks are preceded by warning signs. Recognizing these warning signs and treating symptoms early can help prevent attacks or keep them from becoming worse. Warning signs and symptoms of asthma in adults may include:
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