Allergy In Humans The Tip Of An Iceberg

Roughly one in five Americans suffers from one form or another of allergy. The most common form of allergy is based on an immune reaction called immediate hypersensitivity. Immediate hypersensitivity reactions are called that because the symptoms manifest themselves within minutes of exposure to antigen in sensitized individuals and peak within a few hours.

The list of substances that provoke immediate hypersensitivity responses in humans is virtually endless and may well include almost anything in the biological or chemical environment. Of course, no one person (fortunately) ever develops immediate hy-persensitivity to all possible provoking antigens (called allergens when we are specifically talking about antigens that induce allergic reactions). While some allergens may induce immediate hyper-sensitivity in large numbers of individuals—certain plant pollens; animal dander; house dust—others are as individual as people are: specific drugs or chemicals; a particular brand of makeup; certain foods. The list of symptoms is similarly long: runny noses, itchy eyes, shortness of breath, rashes and eczema, diarrhea, and so on. It's little wonder it took many years before it was determined that all of these various problems and symptoms are related by a common mechanism, let alone that they are all caused by the body's own immune system.

That immediate hypersensitivity reactions in humans are caused by antibodies was suggested by experiments—in part carried out on each other—by two German physicians, Carl Prausnitz and Heinz Küstner. Küstner was allergic to a protein in cooked fish; Prausnitz wasn't. In addition to experiencing distressing symptoms when he ate cooked (but not raw) fish, Küstner also found that when he injected tiny amounts of a protein extract of cooked fish into the skin of his forearm, a rapid and marked reaction ensued. In about 10 minutes a small welt began to arise at the site of injection. It looked very much like a mosquito bite and itched like one. The welt grew rapidly until it was as much as an inch and a half in diameter and was surrounded by a red, patchy region up to four inches across. After about 20 minutes, Küstner began to experience the more generalized, systemic manifestations of a classical hypersensitivity reaction: the itching spread to other parts of his body, he began to cough, and he had difficulty breathing. After another 20 minutes the symptoms leveled off and then slowly drifted back to normal.

The critical part of the experiment involved his colleague Prausnitz, who was not sensitive to fish in any form. When Prausnitz was injected under the skin with the cooked fish extract, absolutely nothing happened, no matter how much was injected or how often. But if Prausnitz was first injected with some of Küstner's serum and a short time later injected under the skin with fish extract, the exact pattern of local swelling and itchiness seen in Küstner developed in Prausnitz.

This experiment demonstrated in the clearest possible way that the agent active causing immediate hypersensitivity in humans circulates in the blood. The skin test developed by Prausnitz and Küstner provided a way of routinely screening for allergy to specific substances in humans; the "P-K" test has been a standard of the allergy clinic for many years.

The antibody responsible for hypersensitivity reactions is called IgE. IgE is one of five major classes of antibodies made by humans (Figure 2.1). B cells specializing in IgE production tend not to hang out in lymph nodes and spleen, but are found in the skin, lungs, and intestinal lining—the points of entry for many pathogens. For some reason, a few individuals seem preferentially to make IgE-type antibodies in response to certain environmental antigens. The first time someone makes IgE antibodies, nothing much happens. For example, an initial bee sting may result in nothing more than the discomfort of the sting itself. But a subsequent sting from the same type of bee may result in a mild or severe hypersensitivity reaction. Why some people make IgE in response to particular antigens and some don't is not well understood.

The reactions that lead to hypersensitivity are due to the unique homing properties of the tail portion of IgE. The initial exposure to allergen triggers the production of IgE. When the IgE antibodies build up to a critical level, they begin to bind to two special immune cells, mast cells and basophils. These cells have Fc receptors on their surface that specifically bind IgE, just as macrophages and neutrophils bind to IgM or IgG antibody tagging bacteria or viruses.

Mast cells and basophils are filled with granules that contain a variety of highly active pharmacological reagents, chief among which is histamine. When antigen (allergen) comes into the system a second time and interacts with this surface-bound form of IgE, the basophils and mast cells are triggered instantly to release the contents of their granules, including histamine, into the bloodstream. It is this degranulation reaction that leads to many of the unpleasant side effects associated with immediate hypersensitiv-ity and allergy.

We know a lot about histamine, and it is clear that together with a few other biochemical components of mast cells and basophils, histamine can account for virtually all of the phenomena associated with immediate hypersensitivity reactions. When histamine binds to blood capillaries, it causes them to enlarge and become more permeable to blood fluids. This is responsible for the rash associated with allergic reactions that take place at the body surface. Of greater concern is the fact that the increased permeability of blood vessels, if it occurs systemically (throughout the body), will also cause a drop in blood pressure and lead to a state of potentially lethal shock.

Another problem caused by histamine is that it binds to the smooth muscle surrounding the bronchioles leading into the air sacs of the lungs, causing them to contract. This leads to a marked constriction of the passageways for air into and out of the lungs. One of the highest concentrations of mast cells in the body is found in the lungs. When histamine is released from mast cells into lung tissue, the resultant constriction of bronchioles becomes a major factor in the respiratory distress, and even respiratory failure, accompanying immediate hypersensitivity reactions. Histamine also triggers mucus-secreting cells to spill more mucus into the airways, further impeding airflow. Air can usually be forced into the lungs by strong, voluntary contractions of the diaphragm (gasping), but subsequent relaxation of the lungs is not strong enough to force the air back out. In the experiments described earlier on anaphylaxis in guinea pigs, autopsy usually showed distended lungs that floated in water. Asphyxiation occurs with the lungs full of stale, used air.

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