Food Allergy Mechanisms

Two types of allergic or hypersensitivity reactions occur as basic immunological mechanisms involved in food allergies. IgE-mediated reactions, also known as immediate hypersensitivity reactions, involve the formation of IgE antibodies that specifically recognize certain allergens in foods.

IgE-mediated reactions are the most important type of food allergy because these reactions involve a wide variety of different foods and the reactions can be severe in some individuals.

IgE-mediated mechanisms are also responsible for allergic reactions to pollens, mold spores, animal danders, insect venoms, and certain drugs; only the source of the allergen differs. Cell-mediated reactions or delayed hypersensitivities probably play an important, although as yet undefined, role in food hypersensitivity.

Celiac disease, may be a form of cell-mediated delayed hypersensitivity. Although Hippocrates was the first to document the occurrence of food allergies, the involvement of the immune system in food allergies was not recognized for many years thereafter.

Prausnitz and Kustner were the first clinicians to recognize that the blood contained some substance that conferred allergic hypersensitivity. They subcutaneously injected a non-allergic individual with a fish extract and noted no adverse reaction.

However, when this same normal individual was first inoculated, under the skin, with serum from a fish-allergic person and then subsequently injected with the fish extract, there was an inflammatory skin reaction at the serum-injected site.

This passive sensitization experiment provided the first evidence that the blood contained some substance that sensitized the allergic individual to the fish. For some years thereafter, this blood factor remained unidentified and was referred to as reaginic factor.

The reaginic factor involved in allergic reactions was first recognized as an antibody in 1966, when Ishizaka et al demonstrated that this reaginic activity was associated with a unique immunoglobulin and tentatively called this protein γE. The protein was officially named immunoglobulin E or IgE by the World Health Organization in 1968.

The identification of IgE as a reaginic antibody provided immunochemical approaches to analyze the mechanisms involved in hypersensitivity reactions. Immunoglobulin E is one of five classes of antibody that are present in the human immune system (the others being IgG, IgM, IgA, and IgD).

The normal function of IgE antibodies is protection from parasitic infections. Although all humans have low levels of IgE antibodies, individuals predisposed to the development of allergies are most likely to produce IgE antibodies that are specific for and recognize certain environmental antigens.

These antigens are typically proteins, although only a few of the many proteins in nature are capable of stimulating the production of specific IgE antibodies in susceptible individuals. The allergens eliciting IgE antibody formation can be found in pollens, mold spores, venoms, dust mites, and animal danders in addition to foods.

The mechanism involved in IgE-mediated reactions is now well understood. In IgE-mediated food allergies, allergen-specific antibodies are first produced in response to stimulus of the antibodyforming B cells in response to the immunological stimulus created by exposure of the immune system to a specific food allergen, usually a naturally-occurring protein present in the food.

The immune response in the small intestine which is responsible for the dominance of the IgE antibody generation is quite complex and involves T helper type 2 cells, interleukin-4 (IL-4), and other factors. The IgE antibodies bind to the surfaces of mast cells in the tissues or basophils in the blood in a process known as sensitization.

The sensitization phase of the allergic reaction is symptomless. In fact, sensitization can occur without the development of clinical reactivity so the demonstration of IgE antibodies directed against a particular food in human blood serum is insufficient evidence for the diagnosis of a food allergy unless it is coupled to a strong history of food allergy or a positive double-blind, placebo-controlled food challenge.

Once sensitized, exposure to the same food allergen on a subsequent occasion can result in an allergic reaction. When this happens, the allergen associates with the mast cell- or basophil-bound IgE, and cross-links two of the IgE molecules.

A series of biochemical events is initiated which causes cell membrane disruption and the release of a variety of mediators contained within granules existing in the mast cells and basophils. The granules in mast cells and basophils contain most of the important mediators of the allergic reaction.

While several dozen substances have been identified as chemical mediators emanating from mast cell and basophils, histamine is responsible for most of the immediate effects of allergic reactions. The histamine-related effects include inflammation, pruritis, and contraction of the smooth muscles in the blood vessels, gastrointestinal tract, and respiratory tract.

Other important mediators include a variety of prostaglandins and leukotrienes; these particular mediators are associated with some of the slower-developing responses observed in some cases of food allergy (e.g. late-phase asthmatic reactions).

While those individuals prone to the development of food allergies may form specific IgE antibodies upon dietary exposure to a particular food, other individuals will not. Even among those individuals predisposed to allergies, exposure to food proteins does not usually result in formation of allergen-specific IgE.

Food-allergic individuals will normally be sensitive to only a few of the wide variety of foods in the typical human diet. In normal individuals, and even in those who are susceptible to the development of food allergies, exposure to a food protein most often results in oral tolerance through induction of T-cell anergy, deletion of reactive T cells, the generation of suppressor T cells, the formation of protective secretory IgA antibodies, and other immunological responses.

Heredity and other physiological factors are significant in predisposing individuals to the development of IgEmediated food allergies and also other environmental allergies. Approximately 65% of patients with clinically documented allergy have first degree relatives with allergic disease.

Conditions that increase the permeability of the intestine to macromolecules, such as viral gastroenteritis, premature birth, and cystic fibrosis, may increase the risk of development of food allergy. Although food allergies may also involve other types of immunological mechanisms.

The IgE-mediated mechanism is, by far, the most well-documented and understood. The mechanism for food-dependent, exercise-induced anaphylaxis is unknown, but enhanced mast cell responsiveness to physical stimuli may be involved. IgE sensitization appears to be involved in many cases.

In contrast to IgE-mediated reactions, the symptoms of cell-mediated allergic reactions do not begin to appear until 6–24 hours after ingestion of the offending food. These reactions develop slowly, reaching a peak at approximately 48 hours and subsiding after 72–96 hours.

The mechanisms of cell-mediated food allergies are not nearly as well understood. They involve an interaction between specific food allergens and sensitized T lymphocytes. Lymphocyte stimulation initiates the release of cytokines and lymphokines which produces a localized inflammatory response.

Antibodies are not involved in these reactions. T lymphocytes are a major component of the gut-associated lymphoid tissue. Except for celiac disease, evidence for the involvement of cellmediated immune reactions in food allergies remains incomplete.

However, cell-mediated reactions appear to be involved in some cases of cows’ milk allergy occurring especially in infants and with symptoms confined primarily to the gastrointestinal tract.

No estimates of the prevalance of cell-mediated food allergies have been made. Celiac disease, also known as celiac sprue or gluten-sensitive enteropathy, appears to be an example of a cell-mediated reaction.

Celiac disease is a malabsorption syndrome occurring in sensitive individuals upon the consumption of wheat, rye, barley, triticale, spelt, and kamut. The role of oats in celiac disease is much less well-defined. Apparently, oats that are totally free of wheat, rye, and barley are safe for celiac sufferers to consume.

The consumption of wheat or other offending grains or products made from these grains elicits inflammatory damage to the absorptive epithelial cells in the small intestine. The absorptive function of the small intestine is compromised as a result. Nutrients are not properly absorbed and water can leak out.

The loss of absorptive function along with the ongoing inflammatory process results in a severe mal-absorption syndrome characterized by diarrhea, bloating, weight loss, anemia, bone pain, chronic fatigue, weakness, muscle cramps, and, in children, failure to gain weight and growth retardation.

The inflammatory mechanism involved in celiac disease is mediated by intestinal T lymphocytes. The gliadin fraction of wheat and related fractions in barley and rye are associated with initiation of celiac disease in susceptible individuals.