The alarmingly increasing frequency of allergies, affecting over 20% of the population in developed countries, has led to the establishment of a new branch of medicine, that of allergology, which is conceptually closely related to immunology.
In a biological sense the term "immunity" refers to the capability of a host to resist or overcome infection caused by a given micro-organism. The protective response of an individual's immune system to an invading agent consists in the recognition of the foreignness of the latter, referred to as an "antigen." This step is followed by 1) the production by "B cells" of selective antibodies (blood proteins), also called "immunoglobulins," which can bind to structurally unique molecular segments of the antigen and which are referred to as "epitopes," or 2) the generation of cytotoxic "T cells" that can recognize specifically the offending agent and subsequently neutralize or kill it. The antigen that triggers the immune response may be also a nonviable foreign body or a sufficiently large molecule to be ingested and "processed" by macrophages of the host, for presentation of the resulting epitopes to the appropriate "helper T (Th) cells," which thus become "specifically" activated. The interaction between appropriate Th and B cells (ie, the activating signal from the Th cells) induces specific B cells to produce the corresponding antibodies.
In 1906 the Austrian physician Clemens von Pirquet coined the word "allergy" to denote an altered immunological reactivity of the host to a foreign substance that leads to diverse harmful effects on re-exposure to that substance (this word originates from the Greek allos, implying deviation from normal behaviour). The foreign substance responsible for a given allergy is called an "allergen."
The immunoglobulins, or antibodies, comprise a family of diverse proteins classified as IgM, IgD, IgG, IgA or IgE. Each antibody molecule reacts selectively with its specific epitope and has a definite function within the overall protective immune response of the host. Thus, the IgE antibodies are uniquely responsible for allergies of the immediate type which are induced in genetically predisposed individuals - for example, allergies to the constituents of various pollens, house dusts, molds, fungi, foods, animal danders and hairs, parasites, insect venoms, latex, various pharmaceutical preparations (eg, penicillin) and some industrial chemicals - in particular those which can react with the proteins of the host.
The serum concentration of IgE antibodies is the lowest among all the immunoglobulins, ie (0.3 µg/ml) and is higher in sera of allergic patients. Because of their low serum concentration, IgE antibodies were discovered only in 1966 by the husband and wife team of Kimishige and Teruko Ishizaka, working at the time in Denver, CO. As a result of the Ishizakases' discovery, a number of pharmaceutical companies produced diagnostic kits for the quantitative determination of human IgE. In turn, the availability of methods to establish the level and the immunological specificity of serum IgE has stimulated studies for the understanding of the molecular and cellular mechanisms underlying immediate hypersensitivity.
IgE antibodies are unique in that they bind tenaciously to special receptors on inflammatory cells; ie, the white blood cells (basophilic leukocytes) and mast cells found in a variety of tissues. Thus, basophils and mast cells (abundant in respiratory and gastrointestinal tracts) in a person who has produced IgE antibodies become coated with these immunoglobulins, which are oriented on the cell membrane in such a way that they can still combine with the epitopes of the inciting allergen. Subsequent exposure of such allergic individuals to the offending allergen results in its binding to the IgE antibodies on the membranes of these cells. This combination induces a perturbation of the cell membrane and the subsequent, almost immediate release from the basophils and mast cells of inflammatory vasoactive compounds; eg, histamine and leukotrienes, eosinophil chemotactic factor of anaphylaxis and platelet-activating factor.
In turn, these substances act rapidly on the smooth muscles of different target organs, resulting in the manifestations characteristic of hypersensitivity diseases (ie, allergies) of the immediate type - for example, hives, itching, sneezing, stomach cramps, nausea, wheezing and asthma in prolonged cases. In severe cases the reaction may result in profound drop of blood pressure, choking and anaphylactic shock. For example, a significant number of people die each year from the systemic effects of allergic responses to drugs such as penicillin, or of the constituents of honeybee venom present in a sting.
It is possible that the capacity to produce IgE reflects an evolutionary protective function of this immunoglobulin, such as for inactivation of parasitic worms and possibly even acting in a "surveillance role" against tumor cells. However, to the sufferers from hayfever, rhinitis and other allergies, the production of IgE results in disease. Normal persons also produce IgE antibodies, but only in extremely small amounts. Therefore, a person who is allergic may be distinguished from one who is not by the amount of IgE produced, and not the production itself. Hence it is not surprising that the levels of histamine and leukotrienes released from mast cells and basophils in allergic persons are substantially higher than those in normal individuals, and that allergic persons are extremely sensitive to minute quantities of allergen.
T-Cell Allergic ReactionsA second type of allergic reaction, involving aggressive T cells rather than IgE antibodies, is represented by the response of some patients to poison ivy and poison oak. This cellular allergic manifestation also underlies different forms of contact dermatitis, which follow direct skin contact with the offending allergens. Drugs such as ampicillin and ordinary industrial chemicals such as formaldehyde and trimellytic anhydride fall into this category. Allergenic compounds may also be found in topical skin creams.
Distribution of Allergies
Allergic disorders are widespread in North America, although the actual distribution of disorders varies with the nature of the allergic response. Allergic diseases, such as hay fever and extrinsic asthma, afflict about 17% of the Canadian population. Clearly, the distribution of allergies caused by environmental allergens, such as the constituents of ragweed pollen, house dust or pet animal dander, is determined by the distribution of the allergen itself. Allergies to ragweed pollen occur mainly in the Eastern provinces, those to grass pollens throughout Canada, and those to the plicatic acid of Western red cedar in British Columbia. Allergies to dietary components occur throughout the country.
Treatment of Allergies
When the offending allergen can be identified, the obvious and most effective treatment is avoidance. If the allergen cannot be avoided, 2 basic strategies of therapy are currently employed. One consists of a series of hyposensitizing injections of the offending allergen, which leads to the production of "blocking antibodies" of the IgG class and, in some cases, to the concomitant reduction in IgE antibodies. The other involves the administration of drugs, such as antihistaminics, which ameliorate the symptoms of allergy without, however, curing the disease.
In recent years, as a result of the application of the methods of molecular biology, allergology has undergone an explosive growth of knowledge by 1) the precise definition of the molecular characteristics of the different factors produced by the cells involved in an allergic reaction; these factors are referred to in a general way as cytokines, or as lymphokines or interleukins (IL) when produced by lymphoid cells, and 2) the synthesis of chemically precisely defined individual allergens which are present in pollens, mites, foods and other complex allergenic materials. Thus, great progress has been achieved in identifying the cellular and molecular signals responsible for the regulation of the synthesis of human IgE.
The current emerging international consensus among allergologists appears to confirm the discovery made in 1989 by Sergio Romagnani in Florence, Italy, that a subset of Th cells (Th2 cells) produce the lymphokines IL-4 and IL-5, which stimulate, respectively, the activation of B cells producing IgE antibodies and the infiltration into the affected organ (eg, the lungs) of eosinophils, which are specialized inflammatory cells. By contrast the release of interferon gamma (IFNy) by the subset of Th1 cells has the opposite effect on the production of IgE. These recent discoveries have established a solid scientific foundation for the development of effective therapeutic strategies for suppressing IgE antibody formation or for inactivating the effector cells (ie, mast cells, basophils and eosinophils) which are responsible for the allergic symptomatology.
Research on the various facets of allergic diseases, in particular in relation to asthma, is being conducted at an internationally competitive level at most medical schools in Canada with the financial support of the Medical Research Council of Canada and Canadian and international pharmaceutical companies. Moreover, allergology is recognized as a specialty area by the Royal College of Physicians and Surgeons of Canada.