The Mechanisms Of Allergic Inflammation – anaphylaxis described
It was nearly 100 years ago–in 1902–that two French scientists discovered the severe allergic condition they named anaphylaxis. Charles Richet. Professor of Physiology at the University of Paris, and his younger colleague Paul Portier had been invited by Prince robert of monaco to participate in oceanographic studies aboard the Prince’s yacht. The Prince suggested they do studies of the toxin produced by a jellyfish, the Portuguese Man-of-War. On their now famous cruise on the mediterranean. Richet and Portier isolated the substance and attempted to immunize and protect dogs against it.
During their experiments, they discovered something unforeseen: subsequent exposures to even smaller doses of the supposedly non-toxic toxin resulted within minutes in a new, unique illness characterized by severe shortness of breath. The animals’ difficulty in breathing culminated in death in less than 30 minutes. Richet and Portier called this illness anaphylaxis. Eventually, anaphylaxis was defined in humans as well.
Anaphylaxis is most often triggered by substances that are injected or ingested. It is medications–especially antibiotics–that are the most frequent source of anaphylaxis. Penicillin is the worst offender, with an incidence of one severe allergic reaction per every 10,000 courses of penicillin therapy. Foods are also significant causes of anaphylaxis and bring about the deaths of 50 to 100 allergic people each year. The foods most likely to induce serious allergic reactions include peanuts, tree nuts, shellfish, fish, eggs and cow’s milk. The venom of stings from bees, wasps, yellow jackets and hornets are another common cause of anaphylaxis today, accounting for UP to 50 deaths per year in the USA and perhaps thousands of severe or potentially life-threatening allergic reactions annually. More recently, we have seen increased reports of severe allergic reactions to latex, the milky sap of the rubber tree used in the manufacture of products such as gloves, medical appliances, condoms, baby pacifiers and balloons.
GETTING TO THE SOURCE OF INFLAMMATION
The trigger of anaphylaxis–or any allergy mediated by immunoglobulin E (IgE) antibodies–is the activation of mast cells and basophils. Mast cells are present in most body tissues (such as the skin, nose, lungs and the gastrointestinal tract), and basophils are found in the blood. IgE antibodies initiate the allergic reaction and are made by the B-lymphocytes of allergic patients in response to an initial exposure to a specific allergen. The cell membranes of all mast cells and basophils have high affinity receptors into which these IgE antibodies fit. These mast cells and basophils are now sensitized and ready to start an allergic reaction upon subsequent allergen exposure. When two or more IgE antibodies have recognized their allergen and linked up with it, they initiate a sequence of biochemical events that activates the mast cell or the basophil.
Pre-formed mediators of inflammation are released immediately; newly formed mediators are generated and released within minutes (see “Phases of an Allergic Reaction,” next page). This acute phase is often referred to as the “immediate” or “early” allergic reaction. The patient experiences sneezing, an itchy, drippy or congested nose, wheezing, coughing, shortness of breath, and even skin swelling, hives or rashes. Symptoms of anaphylaxis can include headache, abdominal pain, vomiting and diarrhea. Later, the individual may go into systemic shock and lose consciousness. Mediators induce these symptoms by causing the smooth muscles of the lung, gastrointestinal tract and blood vessels to contract; the glands in the nose, lungs and elsewhere to secrete mucus; and the blood vessels to dilate and leak fluids into swollen tissue and cause nerve endings to become irritated, resulting in either pain or itching.
About half of all patients move into a so-called “late phase” allergic response some 4 to 6 hours later. This late phase is characterized by an influx of inflammatory cells, especially eosinophils but also neutrophils, monocytes and lymphocytes. This inflammatory influx is orchestrated and modulated by a family of cellular factors called cytokines. The synthesis of cytokines by mast cells or basophils is stimulated by the initial allergic reaction; the cytokines are also derived from lymphocytes and other cells that come into play as the reaction continues.
THE PRE-FORMED MEDIATORS OF INFLAMMATION
The most important pre-formed mast cell or basophil mediator of allergic disease is histamine. When an allergic response begins, histamine is already present in granules in the cytoplasm of the mast cell or basophil; it’s released within minutes once the allergic IgE antibodies and their corresponding allergens cross-link on the mast cell or basophil membrane (see “Before and After,” right). Once in the bloodstream or tissues, histamine heads for specific cell surface histamine receptors, called H1-receptors; present on most cells in the body. Their occupation by histamine results in the symptoms of allergic disease.
The importance of histamine in mediating human allergic disease is made evident by the effectiveness of antihistamine medications. Properly called H1-receptor antagonists, these drugs block histamine from interacting with its receptors. For example, when histamine is injected into the skin, an itchy welt, or “wheal,” surrounded by an area of redness will appear within 15 minutes. If the patient is given an antihistamine before the histamine injection, however, there will be no skin reaction.
THE GENERATED MEDIATORS OF INFLAMMATION
Leukotrienes, or lipoxygenase products, were initially discovered in 1938 as an unidentiffed chemical released during anaphylaxis that was distinct from histamine. It was then referred to as the “slow reacting substance of anaphylaxis” (SRS-A). Not until 40 years later did Bengt Samuelsen and his co-workers at the Karolinska Institute in Sweden fully identify and characterize SRS-A as leukotrienes and document their important role in allergic inflammation.
As described earlier, an allergic reaction prompts the release of histamine, which begins a chain reaction that results in the generation of leukotrienes. Histamine activates the enzyme phospholipase A, which in turn releases arachidonic acid–a fatty acid–from the phospholipid membrane of the mast cell. What is then called arachidonate is acted upon by an enzyme called 5-lipoxygenase and converted to an unstable intermediate chemical–leukotriene A–which is immediately metabolized to form either leukotriene B4 or leukotriene C4, D4 or E4. These leukotrienes, especially leukotriene D4, are more than ten time more potent than histamine. In addition to their constricting effect on bronchial muscle, the leukotrienes also act on blood vessels, causing them to become leaky and resulting in the swelling of the skin. More recently, it’s been shown that leukotrienes are powerful chemoattractants, recruiting eosinophils and thus contributing to the ongoing allergic inflammation. This may explain why a new family of medications, the leukotriene modifiers, have proven effective in the therapy of mild to moderate asthma.
The second family of generated mediators of inflammation–the prostaglandins, or cyclooxygenase products–also have arachidonic acid as their precursor. In this case, however, the arachidonic acid is worked on by the cyclooxygenase enzyme rather than by lipoxygenase. Unlike histamine–which is produced in both mast cells and basophils, prostaglandin D2 (PGD2) is only made in the mast cells. PGD2 is a potent bronchoconstrictor, more powerful than histamine, though less so than the leukotrienes. Elevated PGD2 levels have been measured in secretions aspirated from the lungs of asthmatics and in nasal secretions from patients with nasal allergies. Still, despite high hopes, patients treated with recently-developed prostaglandin modifiers have not shown much improvement; in fact, benefits from this theoretically promising new medicine have yet to be documented.
CYTOKINES AS MEDIATORS OF INFLAMMATION
Cytokines–small proteins that regulate and determine the nature of the immune response–have only recently been postulated as important in allergic inflammation and are thus still the subject of much research. Their role in allergic inflammation is difficult to pin down, due to the tremendous variability and redundancy in their cell source and their biologic activities. Cytokines are made not only in mast cells and basophils but also in practically any cell in the body directly or indirectly involved in the allergic response. They can have either a pro- or anti-inflammatory action depending on their source, their target and what phase of inflammation that target is in when the cytokine is activated.
Several cytokines have been shown to be important in the regulation of IgE synthesis and the accumulation of eosinophils and other inflammatory cells during allergic reactions. The cytokine interleukin 4 (IL-4) has been proven essential for IgE synthesis. IL-4 can also promote the production of IgE antibodies; increased IgE production is the hallmark of allergic disease.
The cytokine interleukin 5 (IL-5) plays a key role in the maturation, activation and survival of eosinophils; increased numbers of eosinophils in the blood and tissues is another characteristic feature of allergic disease. Tumor necrosis factor alpha (TNF-alpha) is another cytokine that is stored preformed within mast cells and is released rapidly after an allergic reaction begins. TNF-alpha regulates the secretion of two additional cytokines, RANTES and eotoxin, which work with IL-5 to attract and activate eosinophils. TNF-alpha also promotes the synthesis of cellular adhesion molecules, which are crucial for inflammatory cell accumulation at the onset of the allergic reaction.
By building upon the discoveries of the past century, we’ve made great strides in our understanding of the mechanisms of allergic disease. Early studies on the mediators released during an allergic reaction focused mainly on histamine. In the 1970s, leukotrienes and other cell membrane-derived products was shown to be important in the allergic reaction. The accumulation of inflammatory cells–especially eosinophils–in allergic reactions was shown to be associated with the production of a variety of cytokines. Most recently, research documenting the role adhesion molecules play in promoting the development of inflammation has added another dimension to the complex molecular network that underlies the pathogenesis of allergic disease. The development of new medications that interfere with the action of cytokines and cellular adhesion molecules is the focus of current research.
These new discoveries are now giving us the opportunity to develop new treatments for this disease. Still, there are many more questions to be asked. It is likely that new insights into the mechanism of allergic disease will offer not only treatment, but perhaps a cure, to the 50 million or more Americans with allergic disease.
RELATED ARTICLE: A PLAN FOR AN ALLERGY ATTACK
Physicians treating allergies can offer their patients three courses of action to be used either separately or in combination: allergen avoidance, medications and immunotherapy. Which course is chosen depends on how practical it is for the patient to avoid an allergen or allergens, as well as the severity and duration of the patient’s symptoms.
People with mild allergies can limit their exposure to household allergens such as dust mites or molds by removing carpets, using a vacuum cleaner with a high-efficiency particulate (HEPA) filter or double bag filter and using zippered, airtight plastic or allergen-proof fabric casings on pillows, mattresses and box springs. Over-the-counter (OTC) medications may also be of use.
For more chronic, disruptive or severe nasal allergies, however, prescription antihistamines generally provide fewer side effects than do OTC antihistamines. Intra-nasal corticosteroids are also commonly used to control the symptoms of nasal allergic disease. Anti-inflammation medications–including cromotyn, leukotriene modifiers and corticosteroids–are used to control asthma. Inhaled beta agonists like albuterol help relieve asthma symptoms as well.
Immunotherapy (allergen vaccinations–also known as allergy shots or hyposensitization) is usually recommended when allergy symptoms are moderate to severe, persist for more than two to three months or are in response to an allergen not easily avoided; in addition, the shots may be necessary for patients who don’t respond well to medication, Immunotherapy works by decreasing the patient’s sensitivity to a particular allergen through the administration of gradually increasing amounts of that allergic material over a period of (typically) three to five years. It is the only treatment that can affect the natural course of the allergic disease process by reducing the patient’s IgE antibodies and allergic status.
The World Health Organization (WHO) recently convened a consensus conference of eminent allergists and immunologists from different parts of the world to discuss the merits of immunotherapy. Their report, which was published early last year, documented the usefulness of immunotherapy. It emphasized the need for careful patient selection and rigorous standards in treatment, including critical attention to the quality of the allergen vaccine. The paper noted that an enhanced knowledge of allergic disease mechanisms may improve immunotherapy in the future. “These advances,” the authors concluded, “should result in new safer and substantially more effective methods of manipulating the human immune response.”
Philip Fireman, M.D., FAAAAI is Professor of Pediatrics and Internal Medicine at the University of Pittsburgh School of Medicine in Pittsburgh, Pennsylvania. He has served as Director of the Allergy and Immunology Training Program of the University of Pittsburgh Health Center and Director of the Section of Allergy and Immunology.
Recipient of multiple National Institutes of Health (NIH) research grants as well as the NIH Research Career Award in Allergy and Immunology, he has been the principal investigator on numerous asthma and allergic rhinitis pharmaceutical research studies. Fireman is the author and co-author of more than 300 scientific publications. His most popular book, Atlas of Allergies, is in its second edition and on CD-ROM.
A member of many scientific organizations, Fireman has been the President of the American Academy of Allergy, Asthma and Immunology and Chair of the American Board of Allergy and Immunology. Currently, he is editor of the American Journal of Rhinology. In addition to his research, Fireman has a clinical practice at the Asthma and Allergic Disease Center of Children’s Hospital and the University of Pittsburgh Medical Center.
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