IgE in Clinical Allergy and Allergy Diagnosis
Updated: July 2015
Originally Posted: May 2003
Jay Portnoy, MD
Professor of Pediatrics
University of Missouri-Kansas City School of Medicine
Division Director of Allergy, Asthma & Immunology
Children's Mercy Hospital & Clinics
Kansas City, MO, USA
In 1919 a physician observed, following a blood transfusion, a case of transient asthma caused by allergy to horse dander. This was the first indication of a factor in blood capable of mediating an allergic reaction. In 1921 Prausnitz & Küstner performed the passive transfer of this substance to artificially induce a positive skin test. The search for reagin started after that, but until the 1960's it was thought that reaginic activity was not a single, indivisible molecular species but was present in allergic sera in the form of labile complexes. This differed radically from immune antibodies that were known at the time.
A new immunoglobulin
In 1966-67 the Ishizaka group in Denver, Colorado, USA, reported on an antiserum that could interfere with reaginic activity. This factor, postulated to represent a new immunoglobulin, was provisionally called yE-globulin. Despite many attempts, the group was unable to purify the yE-globulin, which is now known to be present in extremely low concentrations in serum.
Independently of this work, Bennich and Johansson, in 1965, discovered a new class of immunoglobulins, provisionally called IgND. An atypical myeloma protein was found that shared the known physicochemical properties of reagin. It was shown that the PK reaction could be blocked in a dose-dependent way with isolated IgND or Fc fragments of the ND protein. Using radioimmunoassays, a normal counterpart could be detected in serum of healthy individuals and it was found that patients with allergic asthma had on average a sixfold higher concentration of IgND than normals or patients with non-allergic asthma. A new radioimmunoassay was developed, the radioallergosorbent test (RAST), capable of detecting allergen-specific IgND antibodies to allergen, and their presence in serum correlated with skin test results.
Reagents were exchanged between the laboratories in the USA and Sweden in 1967. It was found that antiserum to yE-globulin reacted with isolated ND protein, and that purified ND protein could block the reaction of anti-yE-globulin in a biological test system for reaginic activity. At the WHO Immunoglobulin Reference Centre in Lausanne, Switzerland in February 1968 the researchers from the two groups met, and it was agreed that the data available on the unique structure, antigenic properties and biological activity of IgND, supported by data on yE-globulin, would allow for the declaration of a new immunoglobulin, which was called IgE.
IgE - a beneficial or pathological molecule?
Based upon the observation that allergic responses typically affect the skin, gut, and respiratory tract, the major sites of parasitic invasion, it is thought that IgE evolved as a defense mechanism against parasitic infestation. Helminths stimulate a vigorous IgE production, including parasite-specific IgE antibody. However, another hypothesis for the beneficial function of IgE antibodies is that they play a key role in very early recognition of foreign material ("gate keeper function") or a general potentiation of the immune system response by improved antigen presentation. Actually, allergy triggered by IgE may provide a beneficial function to the host; the typical allergic reactions of mucus secretion, sneezing, itching, coughing, bronchoconstriction, tear production, inflammation, vomiting and diarrhoea are all mechanisms that expel allergenic proteins from the body.
The role of IgE in allergic inflammation
The immune response in allergy begins with sensitization. When, for example, house dust mite or pollen allergens are inhaled, antigen presenting cells in the epithelium lining of the airways of the lungs and nose, internalise, process and then express these allergens on their cell surface. The allergens are then presented to other cells involved in the immune response, particularly T-lymphocytes. Through a series of specific cell interactions B-lymphocytes are transformed into antibody secretory cells - plasma cells. In the allergic response, the plasma cell produces IgE-antibodies, which, like antibodies of other immunoglobulin isotypes, are capable of binding a specific allergen via its Fab portion. Different allergens stimulate the production of corresponding allergen-specific IgE antibodies. Once formed and released into the circulation, IgE binds, through its Fc portion, to high affinity receptors on mast cells, leaving its allergen specific receptor site available for future interaction with allergen. Other cells known to express high-affinity receptors for IgE include basophils, Langerhans cells and activated monocytes. Production of allergen specific IgE-antibodies completes the immune response known as sensitization.
Re-exposure to allergen
Upon re-exposure, binding of the allergen to IgE orchestrates the immune system to initiate a more aggressive and rapid memory response. Cross-linking of a sufficient number of mast cell/basophil-bound IgE antibodies by allergen initiates a process of intra-cellular signaling, which leads to degranulation of cells, with the release of mediators of inflammation. Mast cells attempt to sustain a fixed number of unoccupied high-affinity IgE receptors on their cell surface. IgE antibodies bind to these receptor sites, waiting for their specific allergen to be encountered. To keep the number of unoccupied IgE receptor sites constant the mast cell regulates IgE receptor expression, probably in response to the levels of circulating IgE.
Early and late phase reactions
The immune system's response to allergen exposure can be divided into two phases. The first is immediate hypersensitivity or the early phase reaction, which occurs within 15 minutes of exposure to the allergen. The second, or late phase reaction, occurs 4-6 hours after the disappearance of the first phase symptoms and can last for days or even weeks. During the early phase reaction chemical mediators released by mast cells including histamine, prostaglandins, leukotrienes and thromboxane produce local tissue responses characteristic of an allergic reaction. In the respiratory tract for example, these include sneezing, oedema and mucus secretion, with vasodilatation in the nose, leading to nasal blockage, and bronchoconstriction in the lung, leading to wheezing. During the late phase reaction in the lung, cellular infiltration, fibrin deposition and tissue destruction resulting from the sustained allergic response lead to increased bronchial reactivity, oedema and further inflammatory cell recruitment. These observations suggest that IgE is instrumental in the immune system's response to allergens by virtue of its ability to trigger mast cell mediator release, leading directly to both the early and late phase reactions.
To see a video of the IgE-mediated allergic response click here.
IgE and the nomenclature of allergic disease
The understanding of the immunological mechanisms underlying allergic disease has led to a revised nomenclature, which relates clinical symptoms to the initiating immunological mechanism. The essence of this new nomenclature can be found in several language translations on the European Academy of Allergology and Clinical Immunology's website. To review the full document click here.
Allergy is defined as "a hypersensitivity reaction mediated by immunological mechanisms" which can be antibody- or cell-mediated. In the majority of cases the antibody typically responsible for an allergic reaction belongs to the IgE isotype and individuals may be referred to as suffering from an IgE-mediated allergic disease, eg, IgE-mediated asthma. Atopy is a personal or familial tendency to produce IgE antibodies in response to low doses of allergens, usually proteins, and, as a consequence, to develop typical symptoms of asthma, rhinoconjunctivitis or allergic skin disease. What is generally known as "atopic eczema/dermatitis" is not one, single disease but rather an aggregation of several diseases with certain clinical characteristics in common, and the term atopic eczema/dermatitis syndrome (AEDS) has been proposed. The subgroup related to allergic asthma and rhinoconjunctivitis, the IgE-associated subgroup of AEDS, can appropriately be called atopic dermatitis/atopic eczema.
Clinical and Laboratory Tests for the Detection of Allergen Specific IgE antibodies
Allergy Skin Tests
Prick skin tests can be used to identify specific IgE sensitization. The skin is marked for testing with a panel of appropriate allergens for the patient, selected on the basis of the clinical history and knowledge of the allergens commonly found in the locality. Positive and negative comparator tests using histamine and saline also should be performed to prove that the skin is capable of demonstrating a positive reaction and to prevent the interpretation of false-positive results occurring as a result of dermatographism.
A variety of methods can used to perform a prick skin test. In one method, a drop of allergen solution is placed onto the skin at each mark, and a fresh fine sterile needle or lancet is used to gently prick the skin through each drop, introducing a minute volume of allergen solution into the dermis. Another method uses a plastic pricking device that delivers a specific amount of allergen to the skin. These can be combined into multiple prickers so that many tests can be applied at one time. After 10-15 minutes the results are interpreted by reference to the control tests. Provided that there is no wheal response to the negative control, the presence of a raised wheal at the site of the allergen skin prick test of 3 mm or greater in diameter indicates the presence of IgE antibodies specific to that allergen. When interpreted in conjunction with the clinical history, the results of skin prick testing can confirm a diagnosis of IgE-mediated disease and identify causal allergens. Skin prick tests are particularly reliable for inhalant allergens. However, the variations in reaction between tests and testers limits it use to experienced personnel. To see a video demonstration of skin prick testing click here.
In-vitro tests for specific IgE antibodies.
The discovery of IgE allowed the development of immuno-assays for IgE and IgE-antibodies, enabling direct and objective measurement of the extent and specificity of the immune response. Immunoassays such as RAST (radio allergosorbent assay),, FAST (fluorescent allergosorbant test) and ELISA (enzyme-linked immunosorbant assay) have been developed each using a different detection system. For each assay, allergens are linked to paper discs or polyurethane caps (ImmunoCAP) and are incubated with the individual's serum. Binding of IgE specific to allergens is detected by the use of an enzyme linked anti-human IgE antibody leading either to a colorimetric or fluorescent product that can be measured. There is a good correlation between the results of serum tests for IgE antibodies, and positive skin and provocation tests, as well as symptoms of allergy. Positive in-vitro results to a specific allergen demonstrate IgE sensitization but are not proof that the allergen is the cause of clinical symptoms.
The measurement of allergen specific IgE antibodies in serum is of similar diagnostic value to that of skin tests but has a much higher reproducibility and is not influenced by ongoing symptoms or treatment, eg, antihistamines or anti-inflammatory therapy. In some instances, especially in food allergic individuals where, in rare cases, even skin prick testing with minute amounts of allergen might cause an anaphylactic reaction, in-vitro tests using blood samples is a safe method to determine levels of specific IgE antibodies. In-vitro tests are also preferred for individuals who have widespread eczema, which precludes skin prick testing.
Approximately 500 different allergens are now available for in-vitro-based allergy diagnosis. In addition to classical pollen, dander and food allergens, drugs, occupational chemicals and recombinant allergens are available. The general availability of well standardized in-vitro allergy tests has greatly improved the quality of allergy diagnosis.
Identification of elevated total IgE as opposed to specific IgE, in serum, secretion or on cell surfaces is of little diagnostic value. The reason is that mitogenic factors in viruses (e.g., Cytomegalovirus - CMV), bacteria (e.g., Staphylococcus), helminths (e.g., Ascaris, Schistosoma) and adjuvant factors in air pollution (e.g., cigarette smoke, and diesel exhaust) stimulate the production of IgE molecules without initiating any allergen specific IgE-sensitization. However, production of IgE-antibodies will increase the total IgE level slightly and thus an increased total-IgE in cord blood is a high sensitivity but low specificity predictor of allergy. A very low total IgE, on the other hand, indicates a low probability of specific IgE sensitization.
Radioallergosorbent tests (RAST)
The discovery of IgE allowed the development of immuno-assays for IgE and IgE-antibodies, enabling direct and objective measurement of the extent and specificity of the immune response. In RAST, allergens are linked to paper discs or polyurethane caps (CAP - RAST) and are reacted with the individual's serum. Binding of IgE specific to that allergen is detected by the use of an enzyme linked anti-human IgE antibody in a colorimetric reaction. Results of RAST testing show a very good corelation between the presence of IgE antibody in serum and positive skin and provocation tests, as well as symptoms of allergy. Positive RAST results to a specific allergen demonstrate specific IgE sensitization but are not proof that the allergen is the cause of clinical symptoms.
The measurement of allergen specific IgE antibodies in serum is of similar diagnostic value to that of skin tests but has a much higher reproducibility and is not influenced by ongoing symptoms or treatment, eg, antihistamines or anti-inflammatory therapy. In some instances, especially in food allergic individuals where, in rare cases, even skin prick testing with minute amounts of allergen might cause an anaphylactic reaction, RAST using blood samples is a safe method to determine levels of specific IgE antibodies. RAST is also the test of choice for individuals who have widespread eczema, which precludes skin prick testing.
Approximately 500 different allergens are now available for RAST-based allergy diagnosis. In addition to classical pollen, dander and food allergens, drugs, occupational chemicals and recombinant allergens are available. The general availability of well standardized in-vitro allergy tests has greatly improved the quality of allergy diagnosis.
Measurement of total IgE, not IgE antibodies, in serum, secretion or on cell surfaces is of little diagnostic value. The reason is that mitogenic factors in viruses (e.g., Cytomegalovirus - CMV), bacteria (e.g., Staphylococcus), helminths (e.g., Ascaris, Schistosoma) and adjuvant factors in air pollution (e.g., cigarette smoke, and diesel exhaust) stimulate the production of IgE molecules without initiating any allergen specific IgE-sensitization. However, production of IgE-antibodies will increase the total IgE level slightly and thus an increased total-IgE in cord blood is a high sensitivity but low specificity predictor of allergy.
The role of atopy in the development of allergic disease
Individuals with a family history of atopy have an increased risk of developing IgE sensitization, and the atopic constitution is also a major risk factor for the development of allergic diseases such allergic asthma, rhinitis or atopic dermatitis/atopic eczema. The contribution of genetic factors to the development of IgE sensitization and to family history of an IgE-mediated disease is between 70-80%. The risk of developing allergic disease in a particular organ is related to family history of that organ-based disease.
Early signs of allergic disease, especially the atopic dermatitis/atopic eczema, and the presence of IgE antibodies specific to inhalant allergens, are important risk factors for later respiratory allergy. IgE antibodies in infant's serum to basic food proteins, e.g., hen's egg, may be predictive of the 'atopic march' (atopic dermatitis/atopic eczema followed by allergic rhinitis and/or asthma).
Can IgE sensitization be prevented?
The mechanisms of primary sensitization are still essentially unknown. Avoidance of allergen exposure has only partially been successful in prevention of IgE-sensitization. Avoidance is difficult to implement and can severely restrict lifestyle, benefits are small, and long-term effects are doubtful. Until recently it has been recommended that infants at high allergy risk may benefit through avoidance of pets and dust mites during the first year of life, but new research suggests that in some individuals, exposure to furry animals (but not to dust mites or cockroaches) may result in immunological tolerance rather than immunological sensitization. A similar finding has been found recently for early introduction of peanut as a way to prevent peanut sensitization in at-risk infants.
Some early respiratory infections, e.g., pertussis and Respiratory Syncitial Virus (RSV) bronchiolitis as well as some forms of gastroenteritis, may enhance IgE-sensitization and thus enhance allergic diseases, although relative lack of early microbial exposure (both gastrointestinal and respiratory) may also enhance the development of allergic diseases. Prevention of IgE sensitization is possible in the occupational environment by the elimination of sensitizing agents from the workplace or implementing measures to prevent employee exposure. Smoking has been shown to be a risk factor for the development of IgE antibodies against occupational agents and has an adjuvant effect with irritant gases, such as ozone and sulphur. So apart from other benefits to health, non-smoking policies in the workplace may have a role to play in preventing IgE sensitization.
A fairly good knowledge exists about the various steps in the allergic reaction, but despite present knowledge, the prevalence of allergic diseases is still increasing. In some areas of the industrialized world up to 50% of the population is affected. More efforts must be dedicated to the understanding of allergic sensitization and how it can be prevented. The identification of the pathological role of IgE and the subsequent release of inflammatory mediators and cytokines has enabled physicians to treat allergic symptoms with regard to the underlying immunological mechanisms. New pharmacotherapy in the form of a humanized monoclonal anti-IgE antibody designed to eliminate IgE may have a valuable role in treating IgE sensitized individuals.