IgE-mediated Allergic Diseases Research Articles

Assessing the effect of 5-hydroxymethylfurfural on selected components of immune responses in mice immunised with ovalbumin.

5-Hydroxymethylfurfural (5-HMF) is one of the most important products of the Maillard reaction. In recent years, many profitable biological effects of this compound have been demonstrated. This study sought to elucidate the anti-allergic effect of 5-HMF by investigating some selected components of the immune response in BALB/c mice immunised with ovalbumin (OVA). Immunised animals had an increased level of serum total and OVA-specific antibodies when compared to the control (P < 0.01).We found that the OVA-induced increase in serum IgE and OVA-specific IgE were significantly suppressed in the groups treated with 5-HMF (P < 0.05). Moreover, interleukin-4 (IL-4) and interferon gamma (IFN-γ) were significantly reduced in a dose-independent manner when compared to the sensitised group (P < 0.05). 5-HMF inhibited the up-regulation of total and OVA-specific IgE through the suppression of the Th2-type immune response in immunised BALB/c mice. 5-HMF could therefore be a novel therapeutic approach for the prevention of IgE-mediated allergic diseases. © 2017 Society of Chemical Industry.

IL-4 Haploinsufficiency Specifically Impairs IgE Responses against Allergens in Mice.

Polymorphisms in genes involved in IL-4 responses segregate with allergic disease risk and correlate with IgE levels in humans, and IL-4 promotes IgE and IgG1 Ab production against allergens in mice. We report that mice with only one intact Il4 gene copy are significantly impaired in their ability to make specific IgE responses against allergens, whereas IgG1 responses to allergens remain unaffected. Il4-hemizygosity also resulted in a modest but detectable drop in IL-4 production by CD4+ T cells isolated from lymph nodes and prevented IgE-dependent oral allergen-induced diarrhea. We conclude that a state of haploinsufficiency for the Il4 gene locus is specifically relevant for IL-4-dependent IgE responses to allergens with the amount of IL-4 produced in the hemizygous condition falling close to the threshold required for switching to IgE production. These results may be relevant for how polymorphisms in genes affecting IL-4 responses influence the risk of IgE-mediated allergic disease in humans.

Peer Relations Among Youth with IgE-Mediated Allergic Disease and Eosinophilic Esophagitis

Peer Relations Among Youth with IgE-Mediated Allergic Disease and Eosinophilic Esophagitis

Association of Polysensitization, Allergic Multimorbidity, and Allergy Severity: A Cross-Sectional Study of School Children

Background: Aeroallergen sensitization is related to the coexistence of allergic diseases, but the nature of this relationship is poorly understood. The aim of this study was to clarify the relationship of polysensitization with allergic multimorbidities and the severity of allergic diseases. Methods: This study is a cross-sectional analysis of 3,368 Korean children aged 6-7 years-old. We defined IgE-mediated allergic diseases based on structured questionnaires, and classified the sensitivity to 18 aeroallergens by logistic regression and the Ward hierarchical clustering method. The relationship of polysensitization (positive IgE responses against 2 or more aeroallergens classes) with allergic multimorbidities (coexistence of 2 or more of the following allergic diseases: asthma, rhinitis, eczema, and conjunctivitis) and severity of allergic diseases was determined by ordinal logistic regression analysis. Results: The rate of polysensitization was 13.6% (n = 458, 95% CI 12.4-14.8) and that of allergic multimorbidity was 23.5% (n = 790, 95% CI 22.0-24.9). Children sensitized to more aeroallergens tended to have more allergic diseases (rho = 0.248, p < 0.001), although the agreement between polysensitization and multimorbidity was poor (kappa = 0.11, p < 0.001). The number allergen classes to which a child was sensitized increased the risk of wheezing attacks (1 allergen: adjusted odds ratio [aOR] 2.22, 4 or more allergens: aOR 9.39), absence from school (1 allergen: aOR 1.96, 3 allergens: aOR 2.08), and severity of nasal symptoms (1 allergen: aOR 1.61, 4 or more allergens: aOR 4.38). Conclusion: Polysensitization was weakly related to multimorbidity. However, the number of allergens to which a child is sensitized is related to the severity of IgE-mediated symptoms.

Human Lactobacillus Strains from the Intestine can Suppress IgE-Mediated Degranulation of Rat Basophilic Leukaemia (RBL-2H3) Cells.

Mast cells play a critical role in immunoglobulin E (IgE)-mediated allergic diseases, and the degranulation of mast cells is important in the pathogenesis of these diseases. A disturbance of the intestinal microflora, especially of endogenous lactic acid bacteria, might be a contributing factor for IgE-mediated allergic diseases. Additional knowledge regarding the interaction of human intestinal Lactobacilli with mast cells is still necessary. Twenty-three strains of Lactobacilli, including commercial and reference strains and strains from the human intestine, were tested for their ability to regulate degranulation of cells from rat basophilic leukemia RBL-2H3 cells (RBL-2H3) in vitro based on a β-hexosaminidase release assay. Each of the tested Lactobacilli characteristically suppressed IgE-mediated degranulation of RBL-2H3 cells, and Lactobacillus GG showed the strongest inhibitory effect on the cells. Furthermore, the bacteria isolated from the human intestine significantly suppressed degranulation of RBL-2H3 cellsin comparison with the reference strains. These results suggest that Lactobacilli, particularly those from the human intestine, can affect the activation of mast cells in a strain-dependent manner. Further study should be conducted to analyse the understanding mechanism.

What Role Does Allergy Play in Chronic Ear Disease and Laryngitis?

IgE-mediated allergy plays a well-established role in both nasal and pulmonary diseases due to the common epithelium and shared mediator responses of the upper and lower airways. This "unified airway" concept has also been described in other sites within the head and neck that contain similar respiratory mucosa: the middle ear and the larynx. This review will highlight the data suggesting a role for IgE-mediated allergic disease in chronic laryngopharyngeal and middle ear disease and the role for allergy testing to aid in diagnosis and treatment of these disorders.

Association between cancer and allergies

BackgroundThe prevalence of allergies and the incidence of cancer are both increasing worldwide. It has been hypothesized that atopy may affect the risk of some cancers.MethodsIn this study, 1525 patients (754 women and 771 men with a mean age of 52.7 ± 11.9 years) with different types of cancer were examined for the presence of allergies. Allergies were confirmed based on retrospective analysis of allergy diagnostic procedures in patients previously diagnosed with cancer. All patients were also analyzed for bronchial asthma and allergic rhinitis according to relevant guidelines. A control group of patients without cancer diagnoses was used for comparison.ResultsPatients with cancer had significantly fewer IgE-mediated allergic diseases than the control population. For the oncological group compared to the non-cancer patients, the odds ratios (ORs) for allergic rhinitis, atopic dermatitis, and bronchial asthma were 0.67 (95 % CI 0.52–0.81), 0.89 (95 % CI 0.78–0.99), and 1.03 (95 % CI 0.91–1.13), respectively. The mean serum concentrations of total IgE were significantly lower in the study population of patients with cancer than in the patients in the control group (45.98 ± 14.9 vs. 83.2 ± 40.1 IU/l; p < 0.05). There were no significant correlations between the type of cancer diagnosed and the form of allergy.ConclusionOur results indicate that the overall incidence of allergies, particularly allergic rhinitis, was lower in patients with some types of cancer. Further studies are needed to confirm our findings.

Laser-facilitated epicutaneous immunotherapy to IgE-mediated allergy

Allergen specific immunotherapy has been shown to be the only effective treatment for long-lasting clinical benefit to IgE-mediated allergic diseases, but a fewer than 5% of patients choose the treatment because of inconvenience and a high risk of anaphylaxis. Recently, epicutaneous allergen-specific immunotherapy (EPIT) has proven effective, yet with limitations owing to strong skin reactions. We demonstrate here safer and faster EPIT, named μEPIT, by delivering powdered allergen and adjuvants into many micropores in the epidermis. We fabricated a microarray patch fractionally coated with a powder mixture of ovalbumin (OVA) model allergen, CpG, and 1,25-dihydroxyvitamin D3 (VD3). Topical application of the patch onto laser-microperforated skin resulted in a high level of epidermal delivery while greatly minimizing allergen leakage into circulation system as compared to current subcutaneous immunotherapy (SCIT). Moreover, only three times of μEPIT over two weeks could sufficiently inhibit allergen-specific IgE responses in mice suffering OVA-induced airway hyperresponsivness (AHR), which was unattainable by eight times of SCIT over three weeks. Mechanistically, μEPIT preferably enhanced IgG2a production suggesting TH1-biased immune responses and induced a high level of T-regulatory (Treg) cells against repeated allergen sensitization. The immune tolerance was confirmed by marked reduction in airway wall thickness as well as eosinophil and neutrophil infiltration into the respiratory airway. The μEPIT represents a novel and painless technology to treat IgE-mediated allergic diseases with little local skin reaction and a minimal risk of anaphylaxis.

Identification of Biological and Pharmaceutical Mast Cell‐ and Basophil‐Related Targets

Identification of Biological and Pharmaceutical Mast Cell‐ and Basophil‐Related Targets

Functional angiotensin and bradykinin receptors are expressed on primary human mast cells

Abstract Purpose The role of mast cells (MCs) has traditionally been recognized as an effector cell for IgE-mediated allergic diseases, involving ~20% of USA citizens. However, everyone has MCs, indicating their involvement in biologic and pathobiologic conditions beyond allergy. Angiotensin converting enzyme inhibitors (ACEI) and angiotensin II type 1 receptor (AT1R) blockers are used to treat cardiovascular disorders such as hypertension, while a bradykinin type 2 receptor (B2R) inhibitor is used to treat attacks of hereditary angioedema. We examined the expression and biological function of AT1R, B2R and B1R on primary human MCs. Methods MCs were dispersed from fresh surgical human skin obtained from CHTN, and placed into culture with SCF (100 ng/ml) for 4–8 weeks. FACS analysis, western blotting, qRT-PCR, degranulation (β-hexosaminidase release), cytokine/chemokine secretion of IL-6, IL-8 and CCL5, nitric oxide (NO) production (DAF-AM diacetate) were measured. Results FACS analysis and western blotting showed the AT1R and B2R are expressed on MCs. Angiotensin II (0.1–10 μM) and bradykinin (BK, 0.1–2 μM) stimulated MCs to release cytokines (1–4 ng/ml) which was inhibited by specific inhibitors. BK also stimulated the production of NO. Both the B2R and B1R are up-regulated by TNFα (10 ng/ml for 3 days), leading to enhanced activation of MCs by BK (1 μM) and desArg-LysBK (1 μM). Exposure of MCs to angiotensin II (2 μM), angiotensin (1–7)(10 μM) or ACEI (ramipril 1 μM) also enhanced cytokine secretion triggered by low concentration of BK (0.03–0.25 μM). Conclusion These findings suggest functional interactions of AT1R, B2R, ACE and Mas on human MCs, providing novel roles for MCs in cardiovascular, inflammatory and allergic disorders.

Qualitative effects of omalizumab on concomitant IgE-mediated disease in a severe asthmatic population: a real life observational study.

Omalizumab is a recombinant humanized monoclonal antibody (anti-IgE) licensed for use in GINA 5 asthma or for chronic idiopathic urticaria. Many patients with asthma have concomitant allergic diseases such as dermatitis and sinusitis. IgE is also implicated in allergic-bronchopulmonary disease (ABPA). In addition, extreme sensitivity to allergen can prevent the initiation of allergen immunotherapy. The aim of this study was to assess the efficacy of omalizumab on symptoms of concomitant non asthmatic IgE-mediated allergic disease in a population of severe GINA 5 in a real life observational setting. This study is a retrospective, observational study assessing patients reported allergic, non-asthmatic symptom response to omalizumab treatment. Fifty-six severe asthmatics treated with omalizumab were studied. Thirty-seven patients had concomitant rhino-sinusitis, 13 had dermatitis and 4 ABPA. Subjects were asked to grade the improvement in their symptom scores on an analogue scale from 0 (no response) to 10 (excellent response). Mean improvement from baseline was 5 and 1.8 in patients with allergic rhino-sinusitis and dermatitis, respectively. Mean improvement from baseline in respiratory symptoms in patients with ABPA was 4.0. The results from our study suggest that omalizumab may have a role in allergic disease outside of its current license.

Inhibition of IgE-Mediated Allergic Reaction By Pharmacologically Targeting the Circadian Clock

Recently, we reported that the circadian clock temporally gates signaling via the high-affinity IgE receptor (FcepsilonRI) in mast cells, thereby generating a marked day–night variation in allergic reactions (JACI, 2014). We therefore hypothesized that pharmacologically resetting the molecular clock in mast cells to times when FcepsilonRI signaling is reduced (i.e., when core circadian protein PERIOD2 [PER2] is up-regulated) might inhibit IgE-mediated allergic reactions. In this study, we determined whether pharmacologically resetting the molecular clock in mast cells or basophils to times when FcepsilonRI signaling was reduced (i.e. when PER2 is up-regulated) resulted in suppression of IgE-mediated allergic reactions. We examined the effects of PF670462, a selective inhibitor of the key clock component casein kinase (CK)1delta/epsilon which up-regulated PER2 in mast cells, on IgE-mediated allergic reactions both in vitro and in vivo. PF670462 suppressed IgE-mediated allergic reactions in mouse bone marrow-derived mast cells or basophils, and the passive cutaneous anaphylactic (PCA) reaction in mice, in association with increased PER2 levels in mast cells or basophils. PF670462 ameliorated allergic symptoms in a mouse model of allergic rhinitis and down-regulated allergen-specific basophil reactivity in patients with allergic rhinitis. Pharmacologically resetting the molecular clock in mast cells or basophils to times when FcepsilonRI signaling is reduced can inhibit IgE-mediated allergic reactions. The results suggest a new strategy for controlling IgE-mediated allergic diseases.

Novel Allergen Immunotherapy Routes

Allergic diseases are among the most common human diseases of humans. Approximately 33 % of the total population in industrialized countries may be affected. The immune response towards allergens is regulated by T lymphocytes and characterized by an interleukin (IL)-4, IL-5 and IL-13 dominated Th2 cytokine profile. Allergen-specific immunotherapy (AIT) is the only causative treatment option and able to change the natural course of disease, e.g., to prevent the development of asthma and new sensitizations. Classically, the allergen extract has been applied subcutaneously to the patient. New application methods for delivering the allergen to the patient have been developed in recent years. The intralymphatic delivery of allergens named intralymphatic immunotherapy (ILIT) has been evaluated in clinical trials and was demonstrated to be a highly potent application route with low effort and side effects while having equal efficacy if compared with current standard AIT forms. However, large studies that verify important questions like optimal dose, injection intervals, new allergen forms, use of adjuvants, etc. are still missing. Moreover, it has to be evaluated, whether different indications like rhinitis, asthma, or atopic dermatitis are suitable for ILIT and whether it is useful in children. Epicutaneous immunotherapy (EPIT) is a possible alternative application form. EPIT is minimally invasive and basically consists of the affixation of allergen containing patches to the epidermis over 6 weeks. From the studies performed so far, the authors concluded, that EPIT is safe and efficacious in a dose-dependent manner after six patches only. EPIT is increasingly attracting attention because of its capacity to offer a safe, needle-free, and potentially self-administrable treatment option for IgE-mediated allergic diseases. AIT is accepted to be the only causative treatment option for allergies. New application routes in ILIT and EPIT may become more important and allow for different delivery methods in the future, however further clinical studies are required and in preparation.

Effects of a Moderately Lower Temperature on the Proliferation and Degranulation of Rat Mast Cells.

Mast cells are traditionally considered as key effector cells in IgE-mediated allergic diseases. However, the roles of mast cells have also been implicated in diverse physiological and pathological processes. Mast cells are distributed in various organs and tissues of various species. Some of the organs and tissues, such as testis, skin, and the upper part of the respiratory tract, have a temperature that is lower than the body's core temperature. The purpose of the present study was to investigate the effects of a lower temperature on the proliferation and degranulation of rat mast cells. Here, we demonstrate that cell growth was retarded at 35°C compared to 37°C for both rat peritoneal mast cells (RPMC) and RBL-2H3, a rat mast cell line. Furthermore, RPMC became more susceptible to degranulation at 35°C compared to 37°C. In contrast, degranulation of RBL-2H3 was not as sensitive to temperature change as RPMC. The functionality of mast cells in unique organs with a lower temperature warrants further analysis.

Debates in allergy medicine: specific immunotherapy efficiency in children with atopic dermatitis

Allergen specific immunotherapy (AIT) has been the only pathogenetically relevant treatment of IgE-mediated allergic diseases (ADs) for many years. The use of AIT for atopic dermatitis (AD) treatment is dubious and has both followers and opponents. The improvement of subcutaneous AIT (SCIT) and introduction of Sublingual immunotherapy (SLIT) gives prospects of their application both for adults and children suffering from AD. This review presents results of scientific research, system and meta-analyses that confirm the clinical efficacy of AIT for children with AD who has the sensitization to allergens of house dust mite, grass and plant pollen suffering from co-occurring respiratory ADs and with moderate and severe course of allergic AD. There have been analyzed the most advanced achievements in AIT studies as well as there have been specified the unmet needs in AD. The preliminary diagnostics of IgE-mediated AD and pathophysiological disorders, including immune ones, will allow a doctor to develop appropriate comprehensive treatment algorithm for children’s AD aimed at its correction. The including of AIT to the children’s comprehensive therapy program is reasonable only if AD has the allergic form. It is necessary better to design the randomized research studies and to acquire extended clinical practice in children with AD. Use of the successes of molecular-based allergy diagnostics will help to optimize and personalize the process of selecting the necessary allergens to determine the most appropriate vaccines for children considering the results of the allergen component diagnostics. The strategy of treatment of children with AD in future will be based on individual target therapy.

Omega-3 long-chain PUFA intake during pregnancy and allergic disease outcomes in the offspring: a systematic review and meta-analysis of observational studies and randomized controlled trials

There is some evidence that increased maternal intake of omega-3 (n-3) long-chain polyunsaturated fatty acids (LC-PUFAs) during pregnancy may reduce the incidence of immunoglobulin E (IgE)-mediated allergic disease. We aimed to evaluate prenatal n-3 LC-PUFA dietary exposure in observational studies and n-3 LC-PUFA supplementation in randomized controlled trials (RCTs) on outcomes of IgE-mediated allergic disease. We conducted searches of the Cochrane Central Register of Controlled Trials, PubMed, Ovid MEDLINE, EMBASE, CINAHL, SCOPUS, and Web of Science to 30 July 2015. We included prospective cohort studies that showed an association between maternal fish or n-3 LC-PUFA intake during pregnancy and RCTs with a prenatal intervention to modify maternal n-3 LC-PUFA intake and outcomes of allergic disease (eczema, rhino-conjunctivitis, asthma) or sensitization in the offspring. A total of 13 publications from 10 prospective cohort studies and 7 publications representing 5 unique RCTs were included. Three RCTs were combined in a meta-analysis for selected outcomes. Nine of 13 observational study publications and 5 of 7 publications from RCTs found a protective association between increased prenatal n-3 LC-PUFA or fish intake and incidence of allergic disease symptoms in the child. Meta-analysis was limited because of the heterogeneity of the RCTs. Pooled results showed a significant reduction in the incidence of "atopic eczema," "any positive SPT [skin-prick test]," "sensitization to egg," and "sensitization to any food" in the first 12 mo of life [RRs (95% CIs): 0.53 (0.35, 0.81), P = 0.004; 0.68 (0.52-0.89), P = 0.006; 0.55 (0.39-0.76), P = 0.0004; and 0.59 (0.46, 0.76), P < 0.0001, respectively]. Our systematic review and meta-analysis was suggestive of benefits of increased n-3 LC-PUFAs in the maternal diet and outcomes of childhood allergic disease. However, due to the inconsistency in results, the hypothesis linking maternal n-3 LC-PUFA intake to childhood allergic disease cannot unequivocally be confirmed or rejected.

Inhibition of IgE-mediated allergic reactions by pharmacologically targeting the circadian clock

The circadian clock temporally gates signaling through the high-affinity IgE receptor (FcεRI) in mast cells, thereby generating a marked day/night variation in allergic reactions. Thus manipulation of the molecular clock in mast cells might have therapeutic potential for IgE-mediated allergic reactions. We determined whether pharmacologically resetting the molecular clock in mast cells or basophils to times when FcεRI signaling was reduced (ie, when core circadian protein period 2 [PER2] is upregulated) resulted in suppression of IgE-mediated allergic reactions. We examined the effects of PF670462, a selective inhibitor of the key clock component casein kinase 1δ/ε, or glucocorticoid, both of which upregulated PER2 in mast cells, on IgE-mediated allergic reactions both in vitro and in vivo. PF670462 or corticosterone (or dexamethasone) suppressed IgE-mediated allergic reactions in mouse bone marrow-derived mast cells or basophils and passive cutaneous anaphylactic reactions in mice in association with increased PER2 levels in mast cells or basophils. PF670462 or dexamethasone also ameliorated allergic symptoms in a mouse model of allergic rhinitis and downregulated allergen-specific basophil reactivity in patients with allergic rhinitis. Pharmacologically resetting the molecular clock in mast cells or basophils to times when FcεRI signaling is reduced can inhibit IgE-mediated allergic reactions. The results suggest a new strategy for controlling IgE-mediated allergic diseases. Additionally, this study suggests a novel mechanism underlying the antiallergic actions of glucocorticoids that relies on the circadian clock, which might provide a novel insight into the pharmacology of this drug in allergic patients.

Presensitization to Ascaris antigens promotes induction of mite-specific IgE upon mite antigen inhalation in mice

BackgroundPatients with house dust mite (HDM) allergy or Ascariasis produce serum IgE specific to the antigens of HDM or nematode Ascaris, respectively. Although human IgE cross-reactivity has been reported between HDM and Ascaris antigens, it remains unclear whether it contributes to the pathogenesis of allergic diseases. We herein investigated the induction of cross-reactive antibodies and T cells in mice and effects of airway exposure to HDM antigens after preimmunization with Ascaris antigens. MethodsMice were intraperitoneally immunized with HDM or Ascaris antigens with Alum, followed by the intranasal administration of HDM antigens. Serum antigen-specific IgE and IgG were measured by ELISA. Cytokine release in splenocytes from Ascaris-immunized mice upon in vitro restimulation with HDM antigens were measured by ELISA. ResultsImmunization with Ascaris or HDM antigens induced cross-reactive IgG1. Splenocytes from Ascaris-immunized mice released IL-5 and IL-13 in response to the restimulation with HDM antigens. Subsequent airway exposure to HDM antigens promoted the induction of HDM-specific IgE and upregulation of HDM-specific IgG1 in Ascaris-immunized mice, whereas these responses were not detected or smaller without the Ascaris presensitization. ConclusionsWe demonstrated that the immunization of naïve mice with Ascaris antigens induced production of antibodies and differentiation of Th2 cells, which were cross-reactive to HDM antigens, and accelerated induction of serum HDM-specific IgE upon subsequent airway exposure to HDM antigens in mice. These results suggest that sensitization to HDM towards IgE-mediated allergic diseases is faster in individuals with a previous history of Ascaris infection than in those without presensitization to Ascaris.

Novel binuclear μ-oxo diruthenium complexes combined with ibuprofen and ketoprofen: Interaction with relevant target biomolecules and anti-allergic potential

This work presents the synthesis and characterization of two novel binuclear ruthenium compounds of general formula [Ru2O(carb)2(py)6](PF6)2, where py=pyridine and carb are the non-steroidal anti-inflammatory drugs ibuprofen (1) and ketoprofen (2). Both complexes were characterized by ESI-MS/MS spectrometry. The fragmentation patterns, which confirm the proposed structures, are presented. Besides that, compounds 1 and 2 present the charge transfer transitions within 325–330nm; and the intra-core transitions around 585nm, which is the typical spectra profile for [Ru2O] analogues. This suggests the carboxylate bridge has little influence in their electronic structure. The effects of the diruthenium complexes on Ig-E mediated mast cell activation were evaluated by measuring the enzyme β-hexosaminidase released by mast cells stimulated by antigen. The inhibitory potential of the ketoprofen complex against mast cell stimulation suggests its promising application as a therapeutic agent for treating or preventing IgE-mediated allergic diseases. In addition, in vitro metabolism assays had shown that the ibuprofen complex is metabolized by the cytochrome P450 enzymes.

Are allergic multimorbidities and IgE polysensitization associated with the persistence or re-occurrence of foetal type 2 signalling? The MeDALL hypothesis.

Allergic diseases [asthma, rhinitis and atopic dermatitis (AD)] are complex. They are associated with allergen-specific IgE and nonallergic mechanisms that may coexist in the same patient. In addition, these diseases tend to cluster and patients present concomitant or consecutive diseases (multimorbidity). IgE sensitization should be considered as a quantitative trait. Important clinical and immunological differences exist between mono- and polysensitized subjects. Multimorbidities of allergic diseases share common causal mechanisms that are only partly IgE-mediated. Persistence of allergic diseases over time is associated with multimorbidity and/or IgE polysensitization. The importance of the family history of allergy may decrease with age. This review puts forward the hypothesis that allergic multimorbidities and IgE polysensitization are associated and related to the persistence or re-occurrence of foetal type 2 signalling. Asthma, rhinitis and AD are manifestations of a common systemic immune imbalance (mesodermal origin) with specific patterns of remodelling (ectodermal or endodermal origin). This study proposes a new classification of IgE-mediated allergic diseases that allows the definition of novel phenotypes to (i) better understand genetic and epigenetic mechanisms, (ii) better stratify allergic preschool children for prognosis and (iii) propose novel strategies of treatment and prevention.