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Immunology: Feature Article
An excerpt of this article was featured in the April 2001 issue of Discover Magazine. Immunology may hold key to future therapies A long misunderstood process within the human body, the immune system is much more than meets the eye. A complex network of cells and organs that protect the body against disease, this vital system has many critical functions, not the least of which is fighting harmful infections. Even in the absence of identifiable disease or infection, the immune system is hard at work keeping us healthy. It only takes one simple "mistake" on the cellular level and our defenses against the outside world can break down, exposing us to a multitude of diseases, including allergies, immune deficiency, asthma and AIDS. "The immune system protects us from outside and inside assaults," said Mark Ballow, MD, FAAAAI, Professor of Pediatrics at SUNY Buffalo School of Medicine and Chief of the Allergy Division at Children’s Hospital in Buffalo, NY. "When people think of the immune system, they think of it as protecting us from infection. That’s true, but a very narrow view. The immune system has a much broader role." The immune system has two major functions: to recognize substances foreign to the body (antigens) and to react against them. Antigens can vary from microorganisms to cancerous cells. As the immune system strives to maintain the "status quo" within the body, it is constantly challenged by bacteria, viruses, fungi and more. Without it, the body has no defense against invading microorganisms, resulting in unchecked infectious disease. The organs of the immune system, or the lymphoid organs, are stationed at the ready throughout the body. Such organs include the bone marrow, thymus, lymph nodes, spleen, tonsils, adenoids and appendix, as well as clumps of lymphoid tissue in the small intestine known as Peyer’s patches. These organs produce, develop and deploy lymphocytes, or the white blood cells that are the key operatives of the immune system, and are carried throughout the body in the blood. Immune cells are destined to either become lymphocytes or phagocytes. Numbering about one trillion within each of us, lymphocytes can be grouped into two classes: T cells and B cells. B cells grow to maturity independent of the thymus, while the T cells are actually processed within the thymus. Both groups of cells recognize specific antigen targets and when a certain target appears, take action in a full-scale attack. Each B cell is programmed to produce one specific antibody, targeting such foreign substances as the common cold virus or even pneumonia. When a B cell encounters its trigger, along with the collaboration of T cells and accessory cells, it creates plasma cells. These cells act as factories to produce large amounts of antibody molecules. An antibody seeks out the circulating antigen and attaches to it much like a key fits in a lock, marking it for destruction. Antibodies are part of the body’s immunoglobulins, or proteins which target individual diseases. Every person has nine distinct classes of human immunoglobulins. Each plays a different role in the immune defense. For example, IgM effectively kills bacteria, while IgG enters tissues and coats microorganisms, preventing them from "sticking" to cells. IgE, which normally occurs in trace amounts in the body, is produced during allergic reactions. This antibody probably evolved as a defense against parasites but for some reason is activated in some individuals by otherwise harmless substances like pollen grains and food proteins. While the B cells are the antibody factories of the body, T cells make the immune system tick. Regulatory T cells, known as helper/inducer cells, actually orchestrate the system and activate B cells, allowing them to produce antibodies. With T and B cells on constant alert, malignancies or marauding parasites are easy targets. Virus-infected cells are at the highest risk since they secrete interferon, a chemical which acts as a radar signal to the body’s natural killer cells. Once spotted by these patrolling cells, T and B cells go to work disabling and destroying the threatening cells. Although our immune system works diligently to protect us from harmful invaders, it still sometimes misses a beat. Scientists are seeking answers to why it sometimes overresponds to substances like pollen, resulting in allergic disease, or why it attacks itself, resulting in autoimmune disorders like arthritis and diabetes. Finding reasons for the immune system’s malfunctions can mean potential new treatments and even cures for allergic disease, asthma, immune deficiency and other disorders. "By understanding how we respond to our environment and why some people overreact to that environment, we can better develop new therapeutic modalities," Ballow said. "As we understand more about these cellular interactions and the products they make and how they are involved in various diseases, we will develop different approaches for therapies. We are on the threshold of seeing some of that research translated into potential approaches for patients. Quality of life is linked to the understanding of our own immune system. It’s so much more than our protection against bacteria and viruses." Immune Deficiency This rise in the number of recognized cases and syndromes is based on a growing understanding of the immune system and the many internal defects that can cause it to malfunction. "This area of science is also exploding because of the human genome project. In 1952 when the first immunodeficient patient was discovered it was by chance. Before that, people always believed that infections were due to the presence of certain unusual germs in the community. No one knew they could occur because of something wrong with the person," said Rebecca H. Buckley, MD, FAAAAI, J. Buren Sidbury Professor of Pediatrics and Professor of Immunology at Duke University Medical Center in Durham, NC. The recognition of immunodeficiency disorders, from severe combined immune deficiency (SCID), or the "bubble boy disease," to Bruton’s Disease, or the body’s failure to produce antibodies in reaction to disease, is rooted in education and awareness, Buckley said. As physicians increase their understanding of these conditions and patients take a more active role in their own health care, proper diagnoses can be made. "It’s a combination of people recognizing them more and even though these are rare diseases, they are probably more common than we realize," Buckley said. "Many patients have been receiving antibiotics for years and this has hidden their underlying condition." These diseases are most frequently recognized in children, since many patients born with such defects in their immune system do not live to see adulthood. The medical community is learning more every day about the numerous genetic defects that affect different parts of the immune system. For example, "bubble boy disease" or SCID affects the body’s T and B cells, essentially disconnecting the entire immune system, leaving the body defenseless against disease. Without a bone marrow transplant or gene therapy to correct the malfunctioning genes, patients have little chance of survival. In other common immunodeficiencies, patients will experience recurrent infections, including sinusitis, bronchitis and pneumonia. Early recognition of immune deficiency and any immune system-related illness is important. With the progress made in the field of immunology in the past 50 years, help is available, Buckley said. "Patients and physicians must be aware that something is wrong," she said. "Every day a new defect and potential new treatment is discovered. These diseases have always been out there and now that they can be recognized, new treatments can be used and patients can be helped. There is hope." HIV/AIDS The largest number of new HIV cases can be found in developing countries where the disease spreads unchecked through unprotected sex, drug use and perinatal transmission during childbirth. In these countries, the rate of children born with HIV infection stands at approximately 1,600 a day, said William T. Shearer, MD, PhD, FAAAAI, Professor of Pediatrics and Immunology at Baylor College of Medicine in Houston and Chief of the Allergy and Immunology Service at Texas Children’s Hospital. "At least 1,500 of these children could be spared the certain death sentence of HIV infection if there were adequate resources to give their mothers antiretroviral medications, or medications to strengthen their immune systems," Shearer said. "Impoverished countries, social mores and government policies all make it virtually impossible for HIV-infected families to receive the medical care they urgently need." Although the spread of HIV in certain segments of developed societies has declined, such as among adult males in the United States, the spread of the disease in undeveloped countries continues at drastically high rates. Mother-to-child transmission during birth remains high. In some countries, more than 50% of mothers giving birth are infected with the virus. Unless treated with intensive antiretroviral therapy, HIV-infected children with their underdeveloped immune systems do not stand a chance against the virus and die within a few years. "The rapid disease process is likely due to the fact that the immune systems of newborns are just beginning to develop at the same time the HIV virus is attacking it and preventing its normal maturation," Shearer said. Without antiretroviral therapy treatment, HIV-infected women have a 20-35% chance of passing the disease on to their infants. With treatment, transmission rates can drop to less than 3%. Despite the growing number of new cases, HIV-infected individuals are living longer and better lives due to advances in the field of immunology. Although aggressive antiretroviral therapy with three or more medications has been a standard treatment for HIV and AIDS, scientists have learned that multi-drug antiretroviral therapy tends to encourage early resistance to the drugs. Holding off on multi-drug therapy when the patient is not experiencing symptoms preserves the use of drugs in the future. The activation of cytotoxic T cells against HIV also is being tested. These structured "drug holidays" can create an auto-vaccination effect resulting in the return of a larger number of helpful T cells. Another exciting study has found that HIV DNA vaccination can boost cellular immunity and protect infected animals from rapid disease progression. Scientists also are exploring the apparent innate immunity that exists in some individuals and prevents them from contracting the virus. The mutation of chemokine receptor CCR5, a molecule that allows HIV to enter the body’s cells, may be the key to this phenomenon. Possibly the most important avenue of research involves better immune-activation strategies to contain the virus, Shearer said, since, unaided, the human immune system cannot contain the growth of HIV. Antiretorviral drugs used to lower the HIV viral load within the body to a low level and activating the body’s T cells represents the best opportunity to eliminate the virus, he said. Since investigators have not yet been able to eradicate the virus from an infected person, it is vital that a vaccine be developed to prevent further spread of the disease, Shearer added. A study with primates has found HIV DNA vaccination can resist the challenge of HIV. "If the spread of HIV infection could be halted by a vaccine, and this accomplished in 25 years, this present HIV plague could be relegated to medical history," he said. "The world waits with trepidation for this medical breakthrough." Atopic dermatitis Allergies affect an estimated 40-50 million people in the United States, or more than 20% of the country’s entire population. One of the most common skin diseases and an allergic disorder, eczema, or allergic dermatitis, is growing in prevalence. Most prevalent among children and infants, this itchy rash-like condition affects more than 15 million in the United States alone. Cases of contact dermatitis and other eczemas result in more than 7 million physician office visits alone each year. Both children and adults can be affected by the social and emotional stress that can also come with the disease due to the disfigurement and visible skin irritation. An inflammation of the skin, atopic dermatitis is rooted within the body’s immune system. When an allergic individual comes in contact with a substance his or her body does not like, namely allergens like dust mites or even food, through external contact or ingestion, the skin becomes itchy and inflamed. Scientists have yet to pinpoint an exact cause of the disease but believe it occurs as a result of a complex interaction between a person’s genes and the environment. Scientists estimate that 65% of patients develop symptoms in the first year of life and 90% before age 5. Onset after age 40 is less common and other skin conditions should be ruled out before a diagnosis of atopic dermatitis is made. Patients are treated with skin hydrating creams and lotions, anti-inflammatory therapy, anti-microbial medication and avoidance. Research into atopic dermatitis continues and promising new treatment options are being explored, but a cure for the disease remains elusive. "For more than 50 years, topical corticosteroids have been the standard form of anti-inflammatory therapy for atopic dermatitis. Topical macrolide immunomodulators are likely to arise as the new form of anti-inflammatory agents which can be used in patients who do not respond well to steroids," said Donald Y.M. Leung, MD, PhD, FAAAAI, Professor and Head of Pediatric Allergy-Immunology at National Jewish Medical and Research Center in Denver. Other new therapies likely will focus on short-circuiting the allergic cascade within the body when the immune system detects a foreign antigen. A new treatment regimen revolves around the theory that an imbalance in the immune system may contribute to the development of atopic dermatitis. Researchers have found that allergic individuals have much larger amounts of the IgE antibody circulating in their blood. Anti-IgE therapy essentially stops the allergic reaction before it starts, allowing the patient to avoid the nasty allergic symptoms of atopic dermatitis. Other molecules, including Interleukin-4, Interleukin-5 and Interleukin-13, have also been found to play major roles in allergic disease. New biologic agents, or drugs based on molecules that occur naturally in the body, will also work to rebalance the immune system. "New drugs and biologicals which inhibit expression of these molecules will be critical in the development of new treatments for atopic dermatitis and all allergies," Leung said. "These drugs would also have the potential to prevent the development of respiratory allergy and asthma since 80% of children with atopic dermatitis also develop asthma and allergic rhinitis." Food allergy Food allergy occurs when our immune system mounts a "misdirected response" against certain proteins in foods. Normally, the gut immune system recognizes food proteins in a very specific manner and differentiates between harmless and potential disease-causing agents that enter the gut. In a food-allergic person, the immune system responds to the harmless food protein by launching a full-scale attack. Allergic antibodies, or IgE, are produced and bind to the surface of different cells, acting like "immunologic antennae." The next time the person eats that specific protein, the antibodies trigger the release of chemicals throughout the body, resulting in sudden symptoms like throat swelling, skin rashes, wheezing, vomiting, diarrhea and even loss of blood pressure. Severe reactions, or anaphylaxis, can be fatal. Approximately 150 people in the United States die each year from food-related anaphylaxis. As with dermatitis, children are largely affected by food allergies, with most food allergies becoming apparent during the first two years of life. According to several renowned food allergy researchers from Mt. Sinai Medical Center in New York, children’s immature guts and immune systems make them an easy target for such allergies. Hugh A. Sampson, MD, FAAAAI; Scott H Sicherer, MD; and Anna Nowak-Wegrzyn, MD, have focused their research efforts on uncovering the mechanisms involved in food allergies. Compared to adults, infants have less capacity to break down food proteins due to reduced acidity in the stomach, decreased activity of digestive enzymes and a weaker gut lining, which could allow for protein penetration. All these factors expose their immature immune systems to potentially allergenic food proteins and allow these proteins to be further distributed throughout the body. Among infants and toddlers, 6-8% experience food reactions, but most outgrow these allergies by their third birthdays. The most common allergies seen in children include egg, cow’s milk, soy, wheat, fish, peanut and tree nut allergies. While children outgrow many allergies, peanut and tree nut allergies tend to linger into adulthood with more than 3 million Americans reporting such allergies. An increased availability of fresh fruits and vegetables from different regions of the world and the population’s more diversified diet have caused an increase in allergies to a variety of foods, including tropical fruits, seeds and vegetables. The reactions to fresh fruits and vegetables often include mouth-itching and often are alleviated or avoided when the food is cooked. Cooking changes the shape of the food proteins in question, making them less likely to pass through the gut barrier. To the immune system, these uncooked food proteins appear the same as those found in certain pollens, creating the troublesome "oral allergy syndrome." Intense research continues in food allergy prevention and treatment. Scientists have learned that delaying the introduction of solid foods to infants until six months of age and breast-feeding are helpful in preventing food allergies. Strong genetic influences also have been uncovered in food allergic patients. This information demonstrates the importance of avoiding certain foods early in life to prevent sensitizing the child. Avoidance also includes the maternal diet, as foods ingested by breast-feeding mothers can be passed to their infants through breast milk. Scientists continue to explore new treatments for food allergy. A new allergic disease treatment, called anti-IgE therapy, may hold promise for the food-allergic. The therapy utilizes a specially devised molecule that attaches to and inactivates the IgE antibodies that cause allergic reactions. Essentially, it stops the allergic reaction before it starts. Besides anti-IgE treatment, research also continues into an effective and safe immunotherapy regimen for food-allergic patients. Immunotherapy consists of a series of injections containing small amounts of an allergen which helps the patient build up an immunity to the offending allergen. Previously, side effects were too great to effectively treat patients for food allergy in this manner, but recent advances in the characterization of food proteins have allowed for new novel treatment forms. Many of the proteins within foods that cause allergic reactions have been identified and purified, their amino acid sequences determined and their DNA codes isolated. With this information, researchers have been able to engineer genetically altered peanut proteins that will not activate IgE, thus turning off the peanut allergic and anaphylactic reaction. Specific anti-allergy molecules, such as bacterial DNA, are also being tested with such vaccines to increase their efficacy. Until a definitive cure or treatment for food allergy is uncovered, avoidance remains the most effective strategy for food-allergic patients. Patients must educate themselves about allergic disease and work with their physicians to manage their conditions. Asthma and the "Hygiene Hypothesis" One of the theories about increasing asthma prevalence has been the intriguing "hygiene hypothesis." According to the theory, we all are born with immature immune systems that, like our central nervous systems, need to be stimulated and "trained" to develop normally. Exposure to microorganisms present in the environment and possibly even infections contracted in infancy may stimulate the immune system, boosting its protective effects against allergy. According to the theory, first proposed in 1989 by epidemiologist David Strachan of the London School of Hygiene and Tropical Medicine, today’s "sterile," Westernized society has led to an increase in allergic diseases. As our society has strived to disinfect its environment and stamp out infectious disease with antibiotics and vaccinations, it has knocked our immune systems out of balance. The National Heart, Lung, and Blood Institute (NHLBI) estimates that asthma is 1.75 times greater in prevalence today than in 1980, and 2.6 times greater for children under age 4. Today, asthma ranks among the most common chronic conditions in the United States. When we limit our exposure to bacteria and infectious diseases, we may be putting ourselves at risk of allergies and asthma, said James E. Gern, MD, FAAAAI, Associate Professor of Pediatrics at the University of Wisconsin-Madison. Children raised in rural environments,, especially those with farm animals, have been found to have a lower incidence of allergies and asthma. Children enrolled in day care early in life and those raised with multiple siblings also have showed a lower prevalence of allergic disease. Even house dust, which harbors a chemical called endotoxin, has been found to challenge a child’s immune system and potentially reduce the risk of allergy. While these facts apparently support the hypothesis, a firm answer for the rising rate of allergic disease still is unknown, Gern said. "One thing that is not explained by the hygiene hypothesis is the current epidemic of asthma in American inner cities. It is generally agreed that the inner city is not a clean environment, and yet allergy and asthma rates are high," Gern said. "This may relate to the fact that asthma is not a single disease and that different factors are driving the asthma trend in this case." With little hard evidence to implicate too much hygiene as the sole reason for allergies and asthma, scientists continue exploring other veins of research, including genetics. Genetic immunity to asthma is apparent in individuals who, although exposed to high levels of allergens in the workplace or home environment, do not develop the disease. A good mix of genes is most likely at work, Gern said. The high incidence of asthma in the inner cities also has been linked to the urban cockroach population. The difficulty in removing cockroach allergen from homes remains a hurdle in preventing asthma and improving quality of life for sufferers. Without saying that all infections are good for us, the hygiene hypothesis has opened some new doors in allergy research, Gern said. Scientists are not simply looking to treat allergies and asthma, they are striving to uncover their roots, which likely lie within the immune system. "The hygiene hypothesis may well explain part of the recent increase in allergic diseases," he said. Future could hold answers Until a cure for immune-related diseases can be uncovered, education and awareness remain a patient’s strongest defense against these diseases. The allergist/immunologist plays an essential role in providing patients with the latest in diagnosis, treatment and management information. Allergist/immunologists and scientists around the world continue to work together in the mission to unlock the mysteries of the human immune system and discover potential cures for disease. Collaboration in the scientific community and the continued research in immunology will likely mean greater quality of life for all of us in the years to come. |
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