Recent years have brought a new understanding of the pathophysiology of allergic conditions. This new knowledge aids greatly in the rational approach to therapy. In order to make such a rational approach, one must be aware of the existence of basic reactions that take place in cells, reactions that give rise to an allergic condition. How do the body cells of an allergic person differ from the body cells of a nonallergic individual?
In order to understand how they differ, we must have some idea of how sensitization takes place. To clarify further reading on the subject, there are two terms that first should be understood: receptors and mediators.
A receptor may be generally described as a specialized reacting surface of a cell (in allergy, the cell is a mast cell or a circulating basophil). Receptors have the capacity to bind with immunoglobulin E (IgE) molecules (IgE molecules formerly were known as reagins). Receptors also react with certain drugs or hormones to produce a response: regulation of the release of substances termed mediators that are normally held within the cell.
A mediator is a chemical substance that induces activity in an excitable tissue, such as muscle or nerve. In allergy the term refers to chemical substances held within the mast cells or circulating basophils - i.e., histamine, slow-reacting substance of anaphylaxis (SRS-A) and eosinophil chemotactic factor of anaphylaxis (ECF-A).
I. THE NORMAL COURSE OF ORIGINAL SENSITIZATION
In allergic sensitization an external antigen enters the body through some opening or because of weakened resistance in the skin or mucosa of the respiratory tract or gastrointestinal tract.
Plasma cells capable of forming IgE (antibody) lie just within the lining of the skin or mucosa. The antigen acts on the plasma cell and causes it to produce IgE. The IgE molecules, in turn, leave the plasma cell and attach firmly to mast cells in circulating basophils. The person is now allergically sensitized (Figure 1).
II. PRODUCTION OF ALLERGIC REACTION
Once a person has been allergically sensitized, he may be exposed to the same antigen causing the sensitization again. In this case, the antigen will enter through the skin or mucosa as before. But now the mast cells are sensitized with the IgE molecules firmly attached to their surface. (Figure 2).
Once a specific antigen * if touches and is bound by two of the IgE molecules, an enzymatic reaction occurs that releases potent chemical mediators (histamine, slow-reacting substance of anaphylaxis, or eosinophilic chemotactic factor of anaphylaxis) from within the cell.
When this occurs in the respiratory tract, these mediators cause contraction of the smooth muscles of the bronchial tree, increased mucus secretion, and the accumulation of eosinophils. When the antigen enters through the skin, the mediators cause vasodilation with redness and edema (urticaria).
There are a number of receptors on the cell surface among which are alpha and beta adrenergic receptors, cholinergic receptors, and prostaglandin receptors. Stimulation of these receptors can regulate the formation and release of the chemical mediators, such as histamine, etc., held within the cell.
It is believed that these receptors regulate the release of mediators by influencing the intracellular level of the cyclic nucleotides, cyclic adenosine monophosphate (c-AMP) and cyclic guanosine monophosphate (c-GMP). This will be explained more fully in the article on "Autonomic Mechanisms in Asthma and other Allergic Diseases" by Dr. Richard J. Summers and Dr. Richard Evans III in this issue of Pediatric Annals.
However, it should be understood that c-AMP inhibits the release of histamine and other mediators from the cell and causes smooth-muscle relaxation. On the other hand c-GMP stimulates the release of histamine and other mediators and causes smooth-muscle contraction.
This knowledge is of great value in the modern therapy of asthma and other allergic diseases. A great many of our most valuable therapeutic agents, such as isoproterenol, isoetharine, metaproterenol, and terbutaline produce improvement in allergic symptoms by their action on the /3-adrenergic receptors increasing c-AMP production, thus bringing about decreased mediator release from the cells and causing smooth-muscle relaxation.
It should be noted that not all allergic symptoms are triggered by allergens; sometimes nonimmunologic factors, such as exercise, air pollution, sudden changes of temperature, low humidity, or infection will be the cause.
A pediatrician who has an understanding of the basic cellular response in an allergic condition and some knowledge of the possible etiological factors can usually determine the proper method of treatment. For example, it is often possible for a patient to avoid the specific allergen involved (e.g., when a child is allergic to dogs or cats). In the case of pollen sensitivities, one can give inoculations of increasing amounts of extracts of the offending allergens until the patient develops adaptive immunity. One can prescribe antihistamines to counteract the amount of histamine causing an allergic reaction, such as is present in mild allergic rhinitis. Or /3-adrenergic drugs may be given that, by stimulating the formation of c-AMP, may prevent the sensitized cells from discharging their mediators (histamine, slow-reacting substance of anaphylaxis, or eosinophil chemotactic factor of anaphylaxis) into the system. Epinephrine, isoproterenol, isoetharine, metaproterenol, and terbutaline are examples of such drugs.
Some scientists, on the other hand, have felt that asthma may be due to an added stimulus to the cholinergic receptor, with increased formation of c-GMP. This would result in increased production and release of histamines from the cell, and constriction of bronchial smooth muscle. If this theory is correct, asthma should respond to a cholinergic antagonist, of which atropine is the best-known example.
This is the first of two issues of Pediatric Annals devoted to the subject of allergy. Both are under the guest editorship of Dr. William A. Howard, Clinical Professor of Pediatrics at George Washington University School of Medicine and Emeritus Chief of the Division of Allergy and Immunology of the Children's Hospital National Medical Center in Washington, D. C. Dr. Howard is very well known in the field of pediatric allergy and has conducted many round-table discussions and seminars on this subject at the meetings and conventions of the American Academy of Pediatrics.
Dr. Howard opens this symposium with a general discussion, "Allergy and Infancy in Childhood." He offers a classification of allergic reactions and manifestations, and this is followed by a discussion of the objectives in treatment and the prognosis of various types of allergy. The article concludes with an excellent list of directions to aid the practicing pediatrician in his personal care of the allergic child.
In the following article, "Diagnostic Approaches in Childhood Allergy," Dr. Howard gives suggestions for taking the history, ordering and evaluating laboratory tests, and finding the specific allergen causing the patient's reaction. Challenge-testing and elimination diets are discussed, as are problems resulting when infection appears to play a significant role in the production of symptoms.
The third article, "Autonomic Mechanisms in Asthma and Other Allergic Diseases," comes from the Walter Reed Army Medical Center and has been written by Lt. Col. Richard J. Summers, M.D., assistant chief of the Allergy-Clinical Immunology Service at Walter Reed, and Col. Richard Evans III, M. D., chief of the Allergy-Clinical Immunology Service. At first glance this article may seem somewhat forbidding to pediatricians who do not have the background in modern immunology that the authors possess. However, if one understands the concept of receptors and mediators that we have discussed above and further realizes that IgE is what was formerly called reagin, the article will be greatly clarified. Theirs is an important and interesting article, and one that should be carefully read if one desires to understand the basic concepts concerning allergy.
The final article in this first issue on allergy deals with "Allergic Dermatoses in Children," and has been prepared by Dr. Andrew M. Margileth, Professor and Associate Chairman of the Department of Child Health and Development, George Washington University School of Medicine, and director of the Outpatient Department at the Children's Hospital National Medical Center.
Dr. Margileth has provided an excellent and very practical review of allergic dermatoses. The article is of particular value in the area of differential diagnosis, and especially in regard to allergic contact dermatitis and contact dermatitis caused by irritating substances. The author reminds us that there are substances in clothes to prevent wrinkling that may cause irritations on the skin, and that the elastic tape in panties and underwear may also be irritative. This informative article also includes advice on prevention, prognosis, and modern methods of treatment.
Next month, Pediatric Annals will be devoted entirely to clinical aspects of allergic therapy. Asthma, allergic rhinitis, and the various modern methods of therapy will be considered.