IgE Molecules Research Articles

HIV-1 induced AIDS is an allergy and the allergen is the Shed gp120--a review, hypothesis, and implications.

The possibility that the induction of T helper 2 (Th2) cytokine synthesis and the gradual increase in interleukin 4 (IL-4) and IgE levels during HIV-1 infection are an allergic response to HIV-1 proteins was raised in the author's previous article [Becker, Virus Genes 28, 1-4, 2004]. The present review extends this hypothesis by citing experimental reports which indicate that HIV-1 shed gp120 virions share a striking resemblance with the allergens that bind to IgE molecules bound to Fc epsilon receptor I-positive (Fc epsilon RI) cells (mast cells, basophils, monocytes, and dendritic cells, DC) and then induce them to release and synthesize the IL-4 cytokine. In the earlier review, it was established that the IL-4 cytokine is responsible for the following processes: IgE synthesis by B cells and the inhibition of antiviral IgG synthesis; the inactivation of T helper 1 (Th1) cells; and the inhibition of the antiviral cytotoxic T cell (CTL) response. The binding of the shed gp120 to B cell-bound immunoglobulin (Ig) depletes these cells. Moreover, it was reported that the viral regulatory proteins Tat and Vpr also stimulate IL-4 release from basophils. The mode of action used by HIV-1 gp120 in the induction of IL-4 [Becker, Virus Genes 28, 1-14, 2004] revealed that the viral protein contains a superantigen (SAg) domain that is capable of binding to the V(H)3 domain of IgE and Ig; namely, the shed gp120 protein act as endogenous and environmental allergens that bind to IgE molecules, which are bound to the Fc epsilon RI receptors on hematopoietic cells. Based on these findings, it is hypothesized that gp120 is an allergen. Consequently, it can be inferred that the active replication of HIV-1 in infected individuals constantly exposes the immune system to an increase in the allergen content until the host immunity is eventually compromised. These finding suggest that HIV-1 engage in a two-pronged attack of the human immune system: it infects Th2 cells, macrophages, and DCs and then replicates at these venues; and the shed gp120 cells cause an allergy. This allergic condition consequently prevents the induction of Th1 cells, cytokine synthesis, and antiviral CTLs that are needed to clear the infecting virus and thus devitalizes the antivirals that are used to treat the virus infection. It was hypothesized [Becker, Virus Genus 28, 1-14, 2004] that the HIV-1 induced allergy can be treated with IL-4 inhibitors or immune response modifiers. A treatment that employs both antivirals and anti-allergen drugs may very well defeat the AIDS syndrome. Another implication of the present hypothesis is the need to improve the viral antigen used for vaccinating healthy individuals against HIV-1 infection. It is thus suggested harmful domains be eliminated from the gp120.

Transfection of a rat cell line with the genes of the human high affinity IgE receptor yields a model mast cell that reacts with human IgE

Rationale Mast cells and basophils are the key players in the course of allergic reactions, secreting a variety of mediators after the cross-linking of receptor-bound IgE molecules by allergens. At present, no appropriate human cell line is available and existing “humanized” cells often have insufficient properties. Therefore, we have established a permanently growing cell line that possesses the required features. Methods Rat basophilic leukemia 2H3 cells, selected for high mediator release, were transfected with the genes coding for the α-chain of the human high-affinity receptor for IgE (FcϵR1). Stable transfectants were characterized by FACS analysis, mobilization of intracellular calcium and mediator release. Results The IgE-binding α-chain of the human receptor is expressed on the cell surface and the “humanized” receptors are functionally integrated into the signaling cascade. The cross-linking of bound human IgE from various sources results in the release of mediators that is much higher than that of any other published transfectant. The transfected cell line has been used to analyze a variety of commercial allergen extracts with respect to their biological activities using the sera of appropriate allergic subjects. Conclusions This cell line will be a valuable tool in the examination of the mechanisms of type I allergy as well as the analysis and standardization of allergens on the basis of their biological activities. In addition, minute amounts of allergenic proteins in complex mixtures, such as foods, can be detected since the assay is very sensitive and directly addresses the allergenicity of the proteins, in contrast to available methods.

Innovative therapies for asthma: anti-IgE -- the future?

Immunoglobulin E was identified in a series of reports by the Ishizakas1 in 1966 as the allergic skin sensitising factor previously known as reagin. Reagin had previously been used to describe the homocytoropic passively transferable substance in serum that was associated with anaphylactic allergy, allergic asthma, and allergic rhinitis. In 1993, Stadler et al.2 described that some murine monoclonal antiIgE antibodies directed against specific epitopes on the IgE molecule had the potential to prevent the biological activity of IgE without being themselves anaphylactogenic. The same group from the Institute of Clinical Immunology at the University of Bern, Switzerland, subsequently demonstrated a specific mouse monoclonal antibody against the site on the IgE molecule that binds with the high-affinity mast cell receptor (FcuRI). They found that the anti-IgE, when bound to the IgE, prevented the binding of the IgE to the mast cell. Since IgE causes disease by the antigenic bridging of IgE molecules on the mast cell with the consequent release of various mediators including histamine and leukotrienes, these investigators concluded that this could result in an antiIgE such as they had studied being a candidate for immunotherapy of IgE mediated disease.

Etiopathogenesis and management of perennial allergic rhinitis: a state-of-the-art review.

Perennial allergic rhinitis is an inflammatory disorder characterized by symptoms of nasal congestion, rhinorrhea, sneezing, and itching. The prevalence of allergic rhinitis is quite common and affects 20% or more of various populations. Some patients with allergic rhinitis are symptomatic only during the pollen season, while many others are allergic to multiple allergens including indoor allergens such as house dust mites, animal dander, cockroaches, and fungi, which lead to perennial symptoms. Immunoglobulin (Ig)-E is the proximate cause of perennial allergic rhinitis. Circulating IgE antibodies bind to the high affinity IgE receptor on mast cells and basophils. IgE antibodies, bound to the receptors crosslinked by allergen, initiate the secretion of inflammatory mediators including histamine, leukotrienes, and cytokines. These mediators can induce both acute and chronic changes that result in symptoms of allergy. Many therapies are approved for the treatment of allergic rhinitis including intranasal corticosteroids, antihistamines with or without decongestants, and nasal cromolyn sodium (sodium cromoglicate). Allergen avoidance is the mainstay of therapy for many patients but is not always practical. For those patients who have not responded to appropriate medications, allergen specific immunotherapy may also be effective.A number of studies with omalizumab have shown that it is effective in the treatment of seasonal allergic rhinitis induced by pollen such as ragweed and birch pollen. Omalizumab is a molecularly cloned humanized monoclonal antibody inhibiting human IgE. It binds specifically to the region of the IgE molecule that binds to the IgE receptor on the mast cell or basophils. Because omalizumab cannot bind IgE molecules that are already bound to the surface receptors on mast cells and basophils, it does not stimulate secretion of mediators from these cells. Omalizumab does not appear to stimulate an immune response against itself. It rapidly reduces free serum IgE levels by over 95% when administered at therapeutic doses and also results in the reduction of IgE receptors on mast cells and basophils. The combined effects of reduction of both free IgE in serum and the receptor density on the mast cells or basophils results in decreased allergen-stimulated mediator release. Preliminary studies in the treatment of perennial allergic rhinitis supports omalizumab's efficacy and safety. The compound has been well tolerated. Aside from urticarial reactions, adverse effects appear to be minimal. Omalizumab is the first of several new immune-based specifically targeted molecules that may prove to be extremely valuable in the treatment of perennial allergic rhinitis, as it is often unresponsive to traditional therapies.

La lignée mastocytaire RBL : modèle expérimental in vitro et application en pharmacologie clinique

The RBL mast cell line was established in 1973. After its adaptation to in vitro culture and the establishment of a histamine-secreting subline (RBL-2H3), this cell line has been a preferential model in fundamental research on mast cells and in pharmacological studies that evaluate the capacity of antagonists to inhibit the degranulation response. Numerous advances on mast cell biology have been achieved using RBL cells. Notably, this model has enabled the precise biochemical characterisation of the high affinity interaction of the IgE molecule with its receptor (FcεRI). It has also allowed the biochemical description and molecular cloning of the α, β and γ subunits that compose the FcεRI as well as the cellular mechanisms initiated by the aggregation of receptor-bound IgE by an allergen. More recently, a model expressing the human FcεRI α chain has been obtained, which allows investigating human IgE functions, as this Ig isotype is species-specific and cannot bind to rodent receptors. It is likely that the RBL model will continue to serve for many years as a basic model system to study the biological properties of mast cells in both fundamental and clinical research applications.

Utilizing Fcε-Bak chimeric protein for studying IgE–FcεRI interactions

We previously constructed a pro-apoptotic Fcε-Bak chimeric protein, targeted against cells expressing the IgE high affinity receptor (FcεRI). We demonstrated that the chimeric protein is internalized by target mast cells and kills them. These results, which constitute a promising basis for applying this approach to antiallergic therapy, raise some theoretical questions with respect to two major issues: (a) is the monomeric Fcε-Bak–FcεRI complex able to undergo endocytosis, and (b) does the receptor binding domain of human IgE (Fcε) react with rodent FcεRI? In an attempt to answer these questions, we have now thoroughly investigate the interaction of human (h) and mouse (m) Fcε-Bak with FcεRI-positive cells. Using established cultures of rodent and human origin, as well as a primary mouse mast cell culture, we demonstrate that binding of the chimeric protein to the membrane is followed by quick endocytosis, leading to the apoptosis of specific cells. We also confirm that this interaction depends on FcεRI and not on other IgE receptors. We found that the effect of Fcε-Bak on the cells depends on the level of surface FcεRI expression, but not on the origin of the target cells or of the Fcε moiety. We suggest that endocytosis of the monomeric Fcε-Bak–FcεRI complex results from the inability of Fcε-Bak to transduce signals, characteristic of the monomeric IgE–FcεRI complex due to the absence of the variable portion of the IgE molecule. Our results also indicate that at least the Fcε fragment of human IgE is able to interact with both human and rodent FcεRI.

Evidence that IgE molecules mediate a spectrum of effects on mast cell survival and activation via aggregation of the FcepsilonRI.

We demonstrate that binding of different IgE molecules (IgEs) to their receptor, FcepsilonRI, induces a spectrum of activation events in the absence of a specific antigen and provide evidence that such activation reflects aggregation of FcepsilonRI. Highly cytokinergic IgEs can efficiently induce production of cytokines and render mast cells resistant to apoptosis in an autocrine fashion, whereas poorly cytokinergic IgEs induce these effects inefficiently. Highly cytokinergic IgEs seem to induce more extensive FcepsilonRI aggregation than do poorly cytokinergic IgEs, which leads to stronger mast cell activation and survival effects. These effects of both types of IgEs require Syk tyrosine kinase and can be inhibited by FcepsilonRI disaggregation with monovalent hapten. In hybridoma-transplanted mice, mucosal mast cell numbers correlate with serum IgE levels. Therefore, survival effects of IgE could contribute to the pathogenesis of allergic disease.

Histamine-releasing factors, a heterogeneous group of different activities.

Histamine-releasing factor or HRF is a collective term used for a heterogeneous group of factors with different modes of action. The current review is focussed on IgE-dependent HRF that require the presence of certain types of IgE (designated IgE+) to induce histamine release. IgE+ might be a structurally different IgE molecule, or, alternatively, autoreactive IgE. A subgroup of IgE-dependent HRF does not bind to IgE, such as cloned HRF p23. This factor turned out to be a basophil-priming cytokine. Alternatively IgE-dependent HRF might be an autoallergen. Several groups demonstrated IgE antibodies to human proteins. However, not all IgE autoallergen-containing extracts induce histamine release of appropriately sensitized basophils. In culture supernatants of human mononuclear cells an autoallergenic activity (Agmn) is found, but no binding to IgE+ was found yet. Agmn might be an autoallergen, since it is cross-reactive with a grass pollen allergen in the stripped basophil assay. IgE-dependent HRF and IgE+ may play a role in the late allergic reaction (LAR). However, IgE+ responsiveness to Agmn (IgEmn+) was not required for a bronchial LAR. IgEmn+ is associated with chronic allergic disease, since the prevalence of IgEmn+ is high in the serum of severe asthmatics and atopic dermatitis patients. Our hypothesis is that exogenous allergens induce IgE antibodies cross-reactive with an endogenous protein. During a LAR, these endogenous proteins are released and the subsequent IgE-mediated reaction prolongs and aggravates the allergic and/or asthmatic symptoms. In conclusion, HRF is a confusing term since it is used for different activities. It might be better to avoid this terminology on and just describe the activity of the factors. Autoallergenic activity is likely to explain most, if not all, IgE-dependent activity.

Synthesis, characterization and immunochemical evaluation of cephalosporin antigenic determinants.

Lack of knowledge of the exact chemical structure of cephalosporin antigenic determinants has hindered clinical interpretation of adverse reactions to these drugs and delayed understanding of the mechanisms involved in the specific recognition and binding of IgE molecules to these antigenic determinants. We further resolve the relationship between structure and activity of proposed antigenic chemicals, including the rational design and synthesis of these haptenic structures. Comparative RAST inhibition studies of the synthesized molecules revealed that they were recognized by IgE antibodies induced by cephalosporin antibiotics. Thus, these data indicate that recognition is mainly directed to the acyl side chain and to the beta-lactam fragment that remains linked to the carrier protein in the cephalosporin conjugation course.

4. IgE, mast cells, basophils, and eosinophils

IgE, mast cells, basophils, and eosinophils constitute essential elements in allergic inflammation. Allergen-specific IgE, synthesized in response to allergens in the environment and in susceptible individuals, becomes fixed to high-affinity receptors on cellular membranes, especially of mast cells and basophils. If these receptor-bound IgE molecules are aggregated on reexposure to specific allergen, these mast cells and basophils produce mediators that result in the allergic response. Principal among the cells drawn to sites of mediator release is the eosinophil. (J Allergy Clin Immunol 2003;111:S486-94.)

Lack of correlation between bronchial late allergic reaction to Dermatophagoides pteronyssinus and in vitro immunoglobulin E reactivity to histamine-releasing factor derived from mononuclear cells

Activity of immunoglobulin (Ig)E-dependent histamine-releasing factor (HRF) is dependent on the IgE molecules bound to the surface of basophils. Sera capable of passively sensitizing basophils to release histamine to HRF were designated IgE+ sera. IgE+ and HRF have been suggested to play a role in late allergic reaction (LAR). The working hypothesis was tested that IgE+ induces a LAR. Further, activity of HRF produced by mononuclear cells (HRF(mn)) was compared with that of recombinant HRF p23. Atopic patients (n = 82) were bronchially provoked with Dermatophagoides pteronyssinus extract and the change in forced expiratory volume in 1 second was monitored. A LAR was defined as forced expiratory volume in 1 second as percentage of baseline < 80% 4 to 10 hours after allergen challenge. The presence of HRF-responsive IgE in serum was determined using basophils sensitized in vitro by serum. The presence of HRF(mn)-responsive IgE (IgE(mn+)) in serum was shown not be essential for a LAR: 63% of the patients with a LAR had no IgE(mn+) in their serum. Further, 71% of patients with IgE(mn+) did not have a LAR. HRF(mn) and recombinant HRF p23 were not equivalent in the bioassay: serum of 38 of 82 atopic patients sensitized basophils to release histamine to HRF(mn), whereas this was found with serum of 1 of 82 patients to HRF p23. The results do not support the hypothesis that IgE(mn+) induces a LAR, but do not exclude the alternative hypothesis that HRFs are released during a LAR and contribute to asthma severity.

From IgE to anti-IgE: where do we stand?

From IgE to anti-IgE: where do we stand?

Rat Monoclonal Anti-Murine IgE Antibody Removes IgE Molecules Already Bound to Mast Cells or Basophilic Leukemia Cells, Resulting in the Inhibition of Systemic Anaphylaxis and Passive Cutaneous Anaphylaxis

IgE plays a central role in allergic reactions. Some anti-IgE antibodies (HMK-12, 6HD5) inhibit the binding of IgE to the FcΕRI of mast cells/basophilic leukemia cells (PT-18, RBL/2H3), but less inhibition is seen with the anti-allotypic JKS-6 and the anti-idiotypic Eb-1. Anti-IgE HMK-12 can detach bound IgE molecules from the FcΕRI. When mast cells or basophils were incubated with monoclonal anti-DNP-IgE SPE-7, washed and treated with anti-IgE HMK-12, anti-IgE/IgE complexes were found in the supernatant. Similar results were obtained with the Fab fragment of HMK-12. Mice injected with anti-DNP-IgE SPE-7 and later with DNP-BSA had the typical systemic anaphylactic shock. However, if they were injected with the anti-IgE antibody (HMK-12) before the challenge, they did not get an anaphylactic shock. In the sera of mice injected with monoclonal IgE SPE-7 and anti-IgE antibody (HMK-12), IgE/anti-IgE complexes were detected. No passive cutaneous anaphylaxis occurred if the rats were injected with anti-IgE antibodies before the challenge. In summary, anti-IgE antibodies can remove IgE antibodies from the FcΕRI; anti-IgE/IgE complexes can be detected in vitro and in vivo, and anti-IgE antibodies can inhibit IgE-mediated systemic or local anaphylactic reactions.

Generation of therapeutic antibody responses against IgE through vaccination.

IgE is the central mediator in atopic allergies such as hay fever, eczema, and asthma; therefore, it is a prime target in the development of allergen-independent preventive treatments. We describe an active immunization strategy that has the potential to reduce IgE to a clinically significant extent. The active vaccine component is a chimeric IgE molecule, Cepsilon2-Cepsilon3-Cepsilon4. The receptor-binding target domain, Cepsilon3, is derived from the recipient species, whereas the flanking domains, Cepsilon2 and Cepsilon4, are derived from an evolutionarily distant mammal. The flanking domains have dual functions, acting both as structural support for the Cepsilon3 domain and to break T cell tolerance by providing foreign T cell epitopes. The efficacy of the vaccine was studied in an ovalbumin-sensitized rat model. Vaccination resulted in antibody responses against IgE in all rats and in a substantial reduction in serum IgE levels in three out of four strains. The skin reactivity upon allergen challenge was significantly reduced in vaccinated animals. The vaccine appears to be safe to use as an antigen. No cross-linking activity was observed in sera of vaccinated animals, and the response to vaccination was reversible with time. Our results suggest that active immunization against IgE has the potential to become a therapeutic method for humans.

Anti-IgE-antibodies in the treatment of allergic diseases

In an established type-I allergy, the IgE molecule is the main mechanism by which the organism specifically recognizes the inhaled allergen. When the IgE molecule is bound to its high-affinity receptor on the surface of a mast cell, it also provides the link between the allergen and the immediate mast cell activation and mediator release, which are the central steps in the type-I immune response. The humanized monoclonal Anti-IgE antibody omalizumab binds to free IgE molecules in the serum and thereby prevents them from attaching to the high affinity IgE-receptors on the mast cell surface. This treatment, when given on a regular basis, is able to block the antigen-induced tissue responses in the bronchi and in the skin. In large scale clinical trials it proved to be effective in controlling allergic asthma, preventing exacerbations and reducing the need for inhaled and/or systemic steroid treatment. In more than 1500 patients treated for at least 1 year, the compound showed excellent safety and tolerability. This new treatment may have an important place in the future treatment of moderate to severe allergic asthma, especially if the patient needs a complex treatment that still allows for recurrent exacerbations. A major advantage of this treatment lies in its ability to control nasal and eye symptoms of the allergic disease at the same time.

New diagnostic tool for differentiation of idiopathic hypereosinophilic syndrome (HES) and secondary eosinophilic states.

The hypereosinophilic syndrome (HES) is a very rare disease, characterized by persistent eosinophilia with tissue involvement and organ dysfunction which often precedes a subsequent T cell lymphoma. Interleukin-5 secreted by a T lymphocyte subpopulation has been described in previous reports as the most important factor responsible for the prolonged lifespan of the eosinophils. The goal of the present study was to describe a fast, simple diagnostic method for the differentiation of HES and secondary eosinophilic states. Beside the surface marker analysis of peripheral blood mononuclear cells (PBMC) we measured surface bound IgE molecules on lymphocytes and eosinophil cells, intracellular cytokines (IL-5, INFgamma) in CD4+ lymphocytes and eosinophil major basic protein (MBP) in eosinophils using flow cytometric detection method. The appearance of an IL-5 producing cell population with a decreased number of INFgamma positive lymphocytes was characteristic for the blood samples of HES patients. Predominance of Th2 cells with the appearance of a CD8+/CD3 /CD56+ cell population was restricted for the HES cases and could not be detected in secondary eosinophilic individuals. Our flow cytometric cytokine detection method (with parallel cell surface marker analysis) does not require cell separation or long term cell culture steps previously described for the detection of IL-5 producing cells. Therefore it seems to be a more appropriate approach for the differential diagnosis of primary and secondary eosinophilic states.

OMALIZUMAB, A MONOCLONAL ANTIBODY AGAINST IgE FOR THE TREATMENT OF ALLERGIC DISEASES

SUMMARYOmalizumab, a recombinant, humanised monoclonal antibody against human IgE, will be introduced soon for the treatment of allergic asthma. This antibody binds circulating IgE molecules and inhibits the type I immune response in the lung and other target organs. In the phase II and III studies performed, it demonstrated a significant and important effect in controlling and stabilising asthma by reducing exacerbations and the need for inhaled corticosteroids. The safety and tolerability up to one year of treatment were very good. This new treatment may have a role in patients with difficult‐to‐control asthma, with recurrent exacerbations, and those with concurrent asthma, nose and eye symptoms.

Assay of spherical cell surface molecules by thermal lens microscopy and its application to blood cell substances.

To detect and quantitate uneven cell surface molecules, such as blood group antigens on a blood cell and immunoglobulin molecules on a mast cell, an improved method of thermal lens microscopy was employed. The antigen molecules were immunologically stained with their antibodies, which were labeled with colloidal gold. Since the surface of the biological cells was not flat but spherical, the focal point of the probe laser beam inevitably deviated from the sample surface on the moving stage. Therefore, the deviation of the focal point of the probe beam was corrected by adjusting the phase of the signal. Using this technique, a three-dimensional antigen distribution on each cell surface was imaged. Despite the convex surface of cells, labeled colloidal gold was correctly quantified. In the measurement of erythrocyte antigens, a small quantity of Lewis antigens was successfully detected on the umbilical cord erythrocytes. Immunoglobulin E on a mast cell, derived from the allergic human mucosa fungus, was also observed by this method, and the distribution of IgE molecules on the cell surface was quantitatively imaged. A thermal lens microscope, which measures spherical samples correcting the deviation, made it possible for us to observe and assay the substances on biological specimens that have complicated forms, such as living cells in vivo or in situ.

Allergic Manifestations as the Results of a Conditional Autoimmune Response

By means of repertoire cloning we have isolated human anti-IgE antibodies as well as human anti-FcΕRI antibodies. Whether the naturally occurring anti-IgE autoantibodies play a pathophysiological role may be disputed, but the beneficial role of recombinant anti-IgE antibodies as a therapeutic agent has been shown. On the other hand, the natural antibodies isolated from an antibody library of a nonallergic individual against the FcΕRI α-chain are anaphylactogenic, if FcΕRI was not occupied. Thus, anti-FcΕRI autoantibodies may be part of a conditional autoimmune reaction, leading to urticaria if local IgE is consumed, e.g. after an immediate reaction. Thus, anti-FcΕRI antibodies may represent an amplification arm of the late reaction. The normal occurrence of anti-IgE and anti-IgE receptor autoantibodies may suggest that it might also be feasible to induce such autoantibodies by vaccination. In a monkey model using a mimotope of human IgE it was possible to induce a beneficial anti- IgE autoimmune response. The actual epitope of the IgE molecule was then also molecularly reconstructed by generating recombinant anti-idiotypic antibodies. These antibodies also induced effectively an anti-IgE response in monkeys, suggesting that not only mimotopes but also anti-idiotypic antibodies may be used to generate an autoimmune response. Both of our projects suggest that active immunization may be a new form of immunomodulation for the treatment of allergic disease.

Why is the prevalence of allergic diseases increasing? A critical assessment of some classical risk factors

presence of Fc«RI-expressing LC/IDEC, bearing IgE molecules, is a prerequisite to provoking eczematous lesions, observed after application of aeroallergens to the skin of atopic patients, strongly supports this concept. Thereby, IgE receptors are the connecting link between the specificity gaining IgE molecules and the APC. However, Fc«RI seems to play the major role in these phenomena. It should be noted that Fc«RI expressed on circulating monocytes may have other functions, mainly in regulating their survival and differentiation outcome. 12 Following the presentation of allergens to T cells, allergen-specific B cells may be activated to produce high amounts of allergen-specific IgE. This IgE may then in turn bind to the Fc«RI on the APC, closing a vicious circle of facilitated antigen presentation. The intermittent or continuous supply of aeroallergens or autoantigens to the process of facilitated antigen presentation may define the pathophysiological basis of the recurrent or self-perpetuating course of AD frequently seen in untreated patients. The successful application of aeroallergens such as cat dander in the recently standardized atopy patch test 13 shows that it is possible to elicit eczematous skin lesions by solely external application of aeroallergens to the skin. Based on the facilitated antigen presentation model of AD, the need for an identification of the individual provocation factors in each patient calls for diagnostic procedures based on the allergen-specific IgE. Cat dander, house dust mite allergens and a variety of food allergens may be successfully avoided following a thoroughly undertaken prick test and in vitro IgE diagnostic evaluation.