IgE, Mast Cell Mechanism, Type 1

Immediate or Type 1 patterns of allergy can largely be attributed to IgE and a subpopulation of immune cells, the mast cells and basophils. These cells are filled with mediators, which are released if an antigen reacts with IgE antibodies, acting as receptors on the cell's surface.

The chemical mediators released by these cells cause allergic symptoms.

The IgE model of allergy is attractive because it is simple and it easy to test for sensitization; the IgE model selects only a special population of people with Type 1, IgE-mediated allergy. While this is an important reaction pattern, some physicians have claimed it is the only valid form of allergic reactions to food. Their opinion is not acceptable. A distinction between immediate, obvious allergic reactions and delayed, less obvious, chronic immune injury is useful.

Stephen J. Gislason MD

Atopy and IgE

The clinical practice of "Allergy" as a specialty has tended to restrict the definition of allergy to one pattern of immune reactivity described as "Atopy" by Coca and Cooke in 1925. The term "atopy" simply meant "strange disease". Allergists noticed connections among the "'strange diseases" including hay fever (seasonal allergic rhinitis and conjunctivitis), asthma and eczema, the three members of the atopic group.

Study of atopic hypersensitivity revealed a common immune mechanism which further confirmed the allegiance of many allergists to atopy, with the exclusion of other allergic diseases from their field of interest. It was found that a single antibody species, IgE or "reaginic antibody", was responsible for some of the typical manifestations of atopy. An inherited tendency to make excessive amounts of IgE antibody is one characteristic of atopic individuals.

IgE reactions tend to be immediate, causing obvious allergic reactions.
IgE-mediated reactions tend to correlate with positive skin and/or RAST tests.

Hay Fever and Allergy Ads

Hay fever is the most clear-cut case of allergy. Ads for antihistamines proclaim the simplest mechanism of allergy:

an inhaled allergen (antigen), grass pollen, meets antibody-coated mast cells waiting in the mucosal surface of the nose

a typical hay fever attack with sneezing, itching and nose congestion results.

A similar reaction in the throat produces soreness, mucus flow, swelling, and difficulty in swallowing and breathing (pharyngitis, laryngitis). A similar reaction in the lungs produces cough, mucus obstruction to airflow, and asthmatic wheezing (bronchitis, asthmatic bronchitis).

The drug, cromolyn, blocks mast cell degranulation and can prevent the whole allergic cascade from developing. Antihistamines, prostaglandin and leukotriene inhibitors knock out a fraction of the subsequent responses. Once underway, corticosteroids are the only drugs that block the late and delayed phase responses. The Type 1 mechanism may activate delayed cell-mediated (lymphocytic) immune responses which extend the disease from hours to days. Repeated antigenic stimulus then prolongs tissue inflammatory events toward chronic disease.

Food antigens can trigger the mast cell mechanism at any point in their journey through the body. Lip, tongue, throat burning and swelling are most obvious. Acute abdominal pain, vomiting, and diarrhea follow. Antigen may not react in GIT but activate Type 1 responses in blood or target organs, especially lungs and connective tissue. The onset of "immediate reactions" may be delayed hours after eating offending foods. Major symptoms include: flushing, swelling, shortness of breath, fast heart rate, panic, pain, and confusion.

Nose Reactions, Skin Tests & Allergy Shots

A convenient correlation between nose-reactive IgE and skin-reactive IgE was discovered. By introducing tiny amounts of suspected antigens into the skin, a local wheal and flare reaction, similar to a mosquito bite, is produced if reactive IgE is present on skin mast cells. The association of hay fever, asthma, and skin tests with allergy practice was further confirmed by the relative success of "allergy shots". These shots came to characterize the allergist's office; other aspects of allergy practice often were neglected.

Allergy shots are immunological treatments. The immune response to any reactive substance can be modified by giving repeated challenges of the reactive substances. Allergy shots for hay fever start with a serum containing the pollen antigens which caused positive skin responses. The antigens are administered in increasing concentrations by regular injections under the skin. It remains unclear how the shots work.

One response to the injected antigen is the production of a second antibody population of the IgG class. These IgG antibodies are thought to compete with IgE antibodies, "blocking" the allergic response. It is also possible that the antigen injections stimulate suppressor T-cells or inhibit helper T-cells and reduce production of IgE.

Allergy shots have limited therapeutic application. The hay fever sufferer and some asthmatics with specific inhalant reactions to grass pollens do well with desensitization. Immunotherapy also protects patients who have had anaphylactic reactions to bee and wasp stings. Patients with complex reactivity, food reactions and drug reactions do not do well with allergy shots, and the shots are not usually recommended. It is our policy to avoid allergy shots in patients who have food allergy and other forms of delayed immune responses.

Neutralization is another immunotherapy technique of repeated injection of antigen at different concentrations. The idea is that if one concentration of antigen will trigger a reaction, another weaker injection will "neutralize" it. Immune cells tested in cell culture in the laboratory do respond differently to different concentrations of antigens. Often they show a biphasic response to a low and to a high dose with no response in the middle. Unfortunately, it is unlikely that the neutralization method has a practical application in living human beings with trillions of cells responding to thousands of antigens at any given moment.

We consume kilogram quantities of food materials daily with thousands of potential food antigens coursing through our body. INs are responding, often in a chaotic manner, to numerous events. Even if single-antigen neutralization worked in controlled circumstances, there is too much chaos happening in our food-consuming lives for this technique to offer practical relief to suffering patients.

Shrinking Definition of Allergy

The reason for the definition of "allergy" to shrink toward a narrowly-defined clinical practice probably was the skin test. If anything distinguished an allergist from his/her colleagues, it was the skin test. By a practical evolution of allergy practice, those clinical problems which were diagnosable by skin reactions became the special property of allergists. Allergy therapy became synonymous with desensitization (immunotherapy) injections.

But, the original definition of the term "atopy" could apply to a larger, ever expanding list of immune-mediated "strange diseases" which plague us at the end of this century of extravagant biological misadventures.

For some time, it has been appreciated that food allergy operates in a more complex and mysterious way than inhaled allergy. Although skin tests were used to test for food sensitivity, many allergists also prescribed various kinds of low allergy or elimination diets on clinical grounds with satisfactory results. Allergists generally appreciated that allergy shots containing food antigens were not helpful. Nevertheless, the IgE model was the easiest route to follow in the study of food allergy.

IgE Triggers Mast Cells and Basophils

Immediate or Type 1 patterns of allergy can largely be attributed to IgE and a sub-population of immune cells, the mast cells and basophils. These cells degranulate if sufficient antigen reacts with IgE antibodies which act as receptors on the cell's surface. An inherited tendency to make excessive amounts of IgE antibody is one characteristic of atopic individuals.

The most explosive, immediate, and obvious allergic reactions begin with allergens attaching to basophil and mast cells triggering their degranulation. Allergens meet reactive cells just under the surface of the skin, respiratory, gastrointestinal and genitourinary tracts. Mast cells release three sets of mediators with dramatic, immediate, local and systemic effects. The big players are histamine, prostaglandins, and cytokines, including leukotrienes B4, C4, D4, E4. All are bronchoconstrictors and increase permeability of blood vessels as in anaphylaxis and asthma.

Three factors recruit and activate other groups of cells which play a major role in extending the immune response for hours to days.

Eosinophils release major basic protein which is damaging to cells.
Neutrophils and basophils supply histamine-releasing factors, prostaglandins and leukotrienes which contribute further to local organ effects; brochoconstriction and edema in the lung are typical effects.
These mediators tend to recruit the next act, the macrophage-lymphocytic response which initiates delayed patterns of "allergy" otherwise know as hypersensitivity disease.

When Pfizer pharmaceuticals launched their new antihistamine, Reactine (cetirizine), they spent a great deal of advertising money educating physicians about the "late-phase response" They claimed that Reactine was more successful in blocking the late-phase response than other antihistamines. The news to many physicians was that there was more to allergy than immediate reactions mediated by histamine. IgE-mediated reactions tended to recruit other immune responses which turned acute events into longer lasting and, possibly, more destructive immune-mediated disease.

The idea of a simple, linear type 1 reaction with histamine as the major mediator released has undergone significant evolution as tissue events have been studied in more detail. Even in the simplest tissue-model, the nasal mucosa reacting to a single exposure to pollen antigen, a biphasic response has been described. A "late-phase" reaction follows hours after the initial reaction. Mast cells release three sets of mediators with dramatic, immediate, local and systemic effects. The big players are histamine, prostaglandins, and cytokines, including leukotrienes B4, C4, D4, E4. All are bronchoconstrictors and increase permeability of blood vessels as in anaphylaxis and asthma. Three chemotactic factors recruit and activate other cells that extend the immune response from hours to days.

For reasons which are not well understood, a variety of patterns of cell recruitment occur in chronic inflammatory states - in chronic rhinitis, for example, there may be a predominately neutrophilic or eosinophilic response. Eosinophils are especially destructive to tissues; they release major basic protein that is damaging to cells. Neutrophils and basophils supply histamine-releasing factors, prostaglandins and leukotrienes which contribute further to local organ effects; bronchoconstriction and edema in the lung are typical effects in asthma triggered by inhaled antigens. These mediators tend to recruit lymphocytic responses which tend to sustain the type 4 or cell-mediated hypersensitivity state in target organs. The complexity of food allergy begins with vagaries of antigen distribution, and extends to the lottery-like variables of cell-recruitment and target organ responses. If the mast cell-IgE mechanism is thought of as a first-line triggering device whose main function is to recruit other immune responses, then the importance of these reactions is better understood.