IgE-mediated Allergic Diseases Research Articles

Association of maternal low-carbohydrate-diet score during pregnancy with allergic diseases at 2 years of age.

We prospectively evaluated the association between low-carbohydrate-diet (LCD) score during pregnancy and the risk of allergic diseases in infants up to 2 years. Participants were from a prospective mother-offspring cohort study in Wuhan, China. LCD score was calculated according to the percentage of dietary energy intake from carbohydrate, protein, and fat assessed in late pregnancy using validated food frequency questionnaires. Allergic diseases, including immunoglobulin E (IgE)-mediated allergic diseases, allergic contact dermatitis, and food allergy, were recorded at 3, 6, 12, and 24 months postpartum follow-up. Poisson regression models were used to calculate relative risks (RRs) and 95% confidence intervals (CIs). Among 1636 mother-infant pairs included in the present analysis, 230 infants (14.1%) with IgE-mediated allergic diseases, 77 (4.7%) with allergic contact dermatitis, and 488 (29.8%) with food allergy were, respectively, reported. Independent of total energy intake and other potential confounders, both the lowest quintile (RR, 1.77; 95% CI, 1.13-2.77) and the highest quintile (RR, 1.72; 95% CI, 1.22-2.63), were associated with the risk of IgE-mediated allergic diseases compared with the middle quintile. Among high-carbohydrate-diet pregnant women, substituting 5% of energy from either protein or fat for carbohydrate was associated with a lower risk of IgE-mediated allergic diseases. While among low-carbohydrate-diet pregnant women, substituting 5% of energy from carbohydrate, especially high-quality carbohydrate, for fat was associated with a lower risk of IgE-mediated allergic diseases. Maternal low carbohydrate-high protein and fat, and high carbohydrate-low protein and fat diet were both associated with an increased risk of allergic diseases in the infants up to 2 years. This study may provide an intervention strategy for allergy prevention in early childhood.

Efficacy of allergen-specific immunotherapy in children with atopic dermatitis sensitized to house dust mites

Background. Allergen-specific immunotherapy is the mainstay of treatment for inducing long-term immune and clinical tolerability of allergens in patients with IgE-mediated allergic diseases. The aim of this study was to investigate the role of sublingual immunotherapy (SLIT) as an adjunct treatment in children with atopic dermatitis sensitized to dust mites by conducting a randomized 18-month clinical trial with house dust mite extract or placebo. Materials and methods. The study included 26 children with atopic dermatitis who were sensitized to house dust mites. 12 patients received SLIT, and 14 controls received only symptomatic treatment. The activity of atopic dermatitis was assessed using the dynamics of SCORAD indicators and the СDLQI questionnaire. Results. After 18 months of treatment, the reduction in baseline SCORAD was 43.4 % in the SLIT group and 10.3 % in the placebo group (W = 104.0, p = 0.003). СDLQI also showed improvement in the SLIT treatment group (40.7 % in the SLIT group, no improvement was found in the control group, W = 106.5, p = 0.004). There were no significant differences in serum Der.p.-specific sIgE levels between the main and control groups 18 months after the start of treatment (p > 0.05). Conclusions. SLIT with dust mite extract can provide significant clinical efficacy among children with atopic dermatitis, as evidenced by a significant overall reduction in SCORAD scores and СDLQI questionnaire scores.

Ambient air pollutants increase the risk of immunoglobulin E-mediated allergic diseases: a systematic review and meta-analysis.

Immunoglobulin E (IgE)–mediated allergic diseases, including eczema, atopic dermatitis (AD), and allergic rhinitis (AR), have increased prevalence in recent decades. Recent studies have proved that environmental pollution might have correlations with IgE-mediated allergic diseases, but existing research findings were controversial. Thus, we performed a comprehensive meta-analysis from published observational studies to evaluate the risk of long-term and short-term exposure to air pollutants on eczema, AD, and AR in the population (per 10-μg/m3 increase in PM2.5 and PM10; per 1-ppb increase in SO2, NO2, CO, and O3). PubMed, Embase, and Web of Science were searched to identify qualified literatures. The Cochran Q test was used to assess heterogeneity and quantified with the I2 statistic. Pooled effects and the 95% confidence intervals (CIs) were used to evaluate outcome effects. A total of 55 articles were included in the study. The results showed that long-term and short-term exposure to PM10 increased the risk of eczema (PM10, RRlong = 1.583, 95% CI: 1.328, 1.888; RRshort = 1.006, 95% CI: 1.003–1.008) and short-term exposure to NO2 (RRshort = 1.009, 95% CI: 1.008–1.011) was associated with eczema. Short-term exposure to SO2 (RRshort: 1.008, 95% CI: 1.001–1.015) was associated with the risk of AD. For AR, PM2.5 (RRlong = 1.058, 95% CI: 1.014–1.222) was harmful in the long term, and short-term exposure to PM10 (RRshort: 1.028, 95% CI: 1.008–1.049) and NO2 (RRshort: 1.018, 95% CI: 1.007–1.029) were risk factors. The findings indicated that exposure to air pollutants might increase the risk of IgE-mediated allergic diseases. Further studies are warranted to illustrate the potential mechanism for air pollutants and allergic diseases.Supplementary InformationThe online version contains supplementary material available at 10.1007/s11356-022-20447-z.

The common triggers of urticaria in children admitted to the pediatric emergency room.

Urticaria frequently causes pediatric emergency department (PED) admissions. Children with urticaria may unnecessarily avoid suspected allergens. We aimed to investigate the possible and exact triggers of urticaria in children admitted to the PED. Medical records of children admitted to the PED within a 1-year period were evaluated for the International Classification of Diseases 10 (ICD-10) L50 urticaria code, noting symptoms, and possible triggers of urticaria. We performed telephone interviews to complete the missing data and further diagnostic tests for IgE-mediated allergies to identify the exact triggers of urticaria. Among 60,142 children, 462 (0.8%) with the L50 code were evaluated. Possible triggers based on the history and physical examination could be identified in 46%: infections (18%), drugs (11%), foods (8%), infections and drugs (3%), insects (3%), pollen (1%), blood products (0.4%), and vaccines (0.4%). The most frequent infections related to urticaria were upper respiratory tract infections (74.5%), urinary tract infections (13.2%), gastroenteritis (8.2%), and otitis media (4.1%). After a diagnostic workup, IgE-mediated allergic diseases were diagnosed in 6% of patients. Twenty-two percent of the patients had multiple PED admission for the same urticaria flare. Urticaria severity was found to be the most important risk factor for readmissions to the PED (odds ratio: 3.86; 95% confidence interval: 2.39-6.23; p < .001). No relationship between urticaria severity, duration, and the triggers was present. Despite detailed diagnostic tests, IgE-mediated allergic triggers were rarely the cause of urticaria in children admitted to the PED. Infections are the most frequent trigger. Severe urticaria causes more frequent readmissions to the PED.

Identification of an immunodominant IgE epitope of Der p 39, a novel allergen of Dermatophagoides pteronyssinus

BackgroundHouse dust mites (HDMs) are the main source of indoor inhalatory allergens that cause IgE-mediated allergic diseases. The discovery and identification of HDM allergens are important for the diagnosis and treatment of allergic diseases. ObjectiveWe sought to identify a Group 39 Dermatophagoides pteronyssinus (Der p) allergen, namely Der p 39, and explore its immunodominant IgE epitopes. MethodsHomology analysis of amino acid (aa) sequences in HDM and human troponin C (TnC)-like protein was performed. Total RNA of Der p was extracted and used to amplify Der p 39 cDNA with specific primers. Recombinant Der p 39 protein was expressed with a pET-His prokaryotic expression system and purified with Ni-NTA resins. IgE binding was evaluated with western blot, dot blot, and enzyme-linked immunosorbent assay (ELISA) experiments. The IgE binding epitopes of Der p 39 were identified by observing HDM-allergic sera interactions with truncated and hybrid proteins formed from Der p 39 and human TnC-like proteins. ResultsThe Der p 39 open reading frame (ORF) cDNA was found to be 462 base pairs and registered in the NCBI library (GenBank no. MZ336019.1). Der p 39, which encoded 153 aa, was found to have 35.63% and 99.35% homology with human TnC and Dermatophagoides farina (Der f) 39, respectively. IgE-ELISA showed IgE binding with expressed and purified recombinant Der p 39 (18 kDa) in 5/87 (5.75%) HDM-allergic sera samples. Analyses of IgE binding with Der p 39-based truncated and hybrid proteins indicated that IgE binding epitopes are likely located in the C-terminal region and dependent on conformational structure. The data from this study were submitted to the World Health Organization and International Union of Immunological Societies (WHO/IUIS) Allergen Nomenclature database. ConclusionDer p 39 was identified as a minor HDM allergen with a conformational IgE binding epitope. These findings could have important theoretical implications in the development of HDM allergy diagnostics and therapeutics.

Inhibitory effects of superoxide dismutase 3 on IgE production in B cells

Immunoglobulin E (IgE) functions as a first-line defense against parasitic infections. However, aberrant production of IgE is known to be associated with various life-threatening allergic diseases. Superoxide dismutase 3 (SOD3) has been found to suppress IgE in various allergic diseases such as allergic conjunctivitis, ovalbumin-induced allergic asthma, and dust mite-induced atopic dermatitis-like skin inflammation. However, the role of SOD3 in the regulation of IgE production in B cells remains elusive. In this study, we investigated the effect of SOD3 on LPS/IL-4 and anti-CD40/IL-4-mediated secretion of IgE in murine B cells. Our data showed that SOD3 can suppress both LPS/IL-4 and antiCD40/IL-7-induced IgE secretion in B cells isolated from both wild-type (SOD3+/+) and SOD3 knock-out (SOD3−/−) mice. Interestingly, B cells isolated from SOD3−/− mice showed higher secretion of IgE, whereas, the use of DETCA, a known inhibitor of SOD3 activity, reversed the inhibitory effect of SOD3 on IgE production. Similarly, SOD3 was found to reduce the proliferation, IgE isotype switch, ROS level, and CCL17 and CCL22 productions in B cells. Furthermore, SOD3 was found to suppress both LPS/IL-4 and anti-CD40/IL-4-mediated activation of downstream signaling such as JAK1/JAK3, STAT6, NF-κB, p38, and JNK in B cells. Taken together, our data showed that SOD3 can be used as an alternative therapy to restrict IgE-mediated allergic diseases.

Guideline on allergen immunotherapy in IgE-mediated allergic diseases: S2K Guideline of the German Society of Allergology and Clinical Immunology (DGAKI), Society of Pediatric Allergology and Environmental Medicine (GPA), Medical Association of German Allergologists (AeDA), Austrian Society of Allergology and Immunology (ÖGAI), Swiss Society for Allergology and Immunology (SSAI), German Dermatological Society (DDG), German Society of Oto-Rhino-Laryngology, Head and Neck Surgery

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Mechanisms and biomarkers of successful allergen-specific immunotherapy.

Allergen-specific immunotherapy (AIT) is considered the only curative treatment for allergic diseases mediated by immunoglobulin E (IgE). Currently, the route of administration depends both on the different types of causal allergens and on its effectiveness and safety profile. Several studies have reported the mechanisms and changes in humoral and cellular response underlying AIT; however, the full picture remains unknown. Knowledge of who can benefit from this type of treatment is urgently needed due to the patient safety risks and costs of AIT. In vivo or in vitro biomarkers have become a strategy to predict clinical outcomes in precision medicine. There are currently no standardized biomarkers that allow determining successful responses to AIT, however, some studies have found differences between responders and nonresponders. In addition, different candidates have been postulated that may have the potential to become biomarkers. In this review, we aim to summarize the findings to date related to biomarkers in different IgE-mediated allergic diseases (respiratory, food, and venom allergy) with the potential to define who will benefit from AIT.

Allergen-specific immunotherapy practices and course of coronavirus disease 2019 (COVID-19) in patients during COVID-19.

BackgroundAllergen-specific immunotherapy (AIT) is accepted as the only disease-modifying therapy for IgE-mediated allergic airway diseases and hymenoptera venom allergy. AIT requires repeated contact between patient and physician or nurse in the hospital. Because it is a long-term treatment, compliance is essential issue to obtain maximal efficacy. Coronavirus disease 2019 (COVID-19) pandemic reshaped doctor-patient interaction and pattern of hospital admissions.ObjectiveWe aimed to determine the possible changes in the administration of AIT and associated factors, in addition to the characteristics of patients diagnosed with COVID-19 infection.MethodsAdult patients who underwent AIT for hymenoptera venom allergy, allergic rhinitis or allergic asthma between 11 March 2020 and 31 January 2021 were included in our retrospective study. Perennial and preseasonal AIT practices were evaluated. We identified patients with COVID-19 infection among the ones who received AIT.ResultsThe mean age of 215 patients was 37.8±11.9 years and 52.1% of the patients were female. In our study, 35.4% of perennial AIT patients did not continue treatment after the COVID-19 pandemic, and the cause was patient-related in 66.7% of the cases. Compliance was 70.7% in patients receiving perennial AIT. The highest compliance rate for AIT was for venom allergy (86.5%). Thirty-four patients (15.8%) were diagnosed with COVID-19 infection. No mortality due to COVID-19 infection was observed in those who underwent AIT.ConclusionCOVID-19 pandemic has reduced compliance to AIT. Compliance was higher in venom immunotherapy than in aeroallergens. Severe COVID-19 infection and COVID-19 related death were not observed in patients receiving AIT.

Specific molecular and laboratory tests in allergic diseases

Allergic diseases have experienced an increasing prevalence in recent decades throughout the world, including in Romania. They affect a large number of people, generating high costs for the public health system, absenteeism from the workplace and altering the patient’s quality of life, including an increased risk of death. Currently, specific molecular and laboratory tests are increasingly used for the diagnosis of allergic conditions, as they present multiple advantages over traditional in vivo tests. Molecular tests are based on the use of purified or recombinant natural allergens, and there are several singleplex or multiplex testing platforms. These platforms contain the main respiratory and food allergens that are responsible for producing allergic reactions. The molecular diagnosis of allergies was included in the diagnostic algorithm according to the EAACI guide, being subsidized in some states of the European Union, which is why we propose a set of precision paraclinical investigations for the diagnosis and monitoring of IgE-mediated allergic diseases with severe forms, and/or with risk and/or with comorbidities through specific molecular and laboratory tests of patients with allergic conditions, based on the EAACI recommendations.

Flavoring agent dihydrocoumarin alleviates IgE-mediated mast cell activation and allergic inflammation.

Mast cells (MCs) are the main effector cells in the onset of high-affinity receptor for IgE (FcεRI)-mediated allergic diseases. The aim of this study was to test whether dihydrocoumarin (DHC), a food flavoring agent derived from Melilotus officinalis, can block IgE-induced MC activation effects and to examine the potential molecular mechanisms by which DHC affects MC activation. Rat basophilic leukemia cells (RBLs) and mouse bone marrow-derived mast cells (BMMCs) were sensitized with anti-dinitrophenol (DNP) immunoglobulin (Ig)E antibodies, stimulated with DNP-human serum albumin antigen, and treated with DHC. Western blot analyses were performed to detect the expression of signaling proteins. Murine IgE-mediated passive cutaneous anaphylaxis (PCA) and ovalbumin (OVA)-induced active systemic anaphylaxis (ASA) models were used to examine DHC effects on allergic reactions in vivo. DHC inhibited MC degranulation, as evidenced by reduced β-hexosaminidase activity and histamine levels, and reduced morphological changes associated with MC activation, namely cellular elongation and F-actin reorganization. DHC inhibited the activation of MAPK, NF-κB, and AP-1 pathways in IgE-activated MCs. Additionally, DHC could attenuate IgE/Ag-induced allergic reactions (dye extravasation and ear thickening) in PCA as well as OVA challenge-induced reactions in ASA mice (body temperature, serum histamine and IL-4 secretion changes). In conclusion, DHC suppressed MC activation. DHC may represent a new MC-suppressing treatment strategy for the treatment of IgE-mediated allergic diseases.

Single-cell characterization of dog allergen–specific T cells reveals TH2 heterogeneity in allergic individuals

Allergen-specific type 2 CD4+ TH2 cells are critically involved in the pathogenesis of IgE-mediated allergic diseases. However, the heterogeneity of the TH2 response has only recently been appreciated. We sought to characterize at the single-cell level the exvivo phenotype, transcriptomic profile, and T-cell receptor (TCR) repertoire of circulating CD4+ T cells specific to the major dog allergens Can f 1, Can f 4, and Can f 5 in subjects with and without dog allergy. Dog allergen-specific memory CD4+ T cells were detected exvivo by flow cytometry using a CD154-based enrichment assay and single-cell sorted for targeted gene expression analysis and TCR sequencing. Dog allergen-specific T-cell responses in allergic subjects were dominantly of TH2 type. TH2 cells could be phenotypically further divided into 3 subsets, which consisted of TH2-like (CCR6-CXCR3-CRTH2-), TH2 (CCR6-CXCR3-CRTH2+CD161-), and TH2A (CCR6-CXCR3-CRTH2+CD161+CD27-) cells. All these subsets were nonexistent within the allergen-specific T-cell repertoire of healthy subjects. Single-cell transcriptomic profiling confirmed the TH2-biased signature in allergen-specific T cells from allergic subjects and revealed a TH1/TH17 signature in nonallergic subjects. TCR repertoire analyses showed that dog allergen-specific T cells were diverse and allergic subjects demonstrated less clonality compared to nonallergic donors. Finally, TCR and transcriptomic analyses revealed a close relationship between TH2-like, TH2, and TH2A cells, with the last ones representing the most terminally differentiated and highly polarized subtype. Our study demonstrates heterogeneity within allergen-specific TH2 cells at the single-cell level. The results may be utilized for improving immune monitoring after allergen immunotherapy and for designing targeted immunomodulatory approaches.

Pollen Sensitization in Association with Allergic Rhinitis in preschool asthmatic Children

Abstract Background Grass pollens are significant elicitors of IgE-mediated allergic disease in the world and timothy grass (Phleum pratense) is an important pollen in allergy induction. Objective We sought to determine the rate of pollen sensitization in group of Egyptian asthmatic children with allergic rhinitis using timothy grass pollen as a potential triggering factor for allergic rhinitis. Patients and Methods This analytical cross sectional study was conducted on a group of preschool children following up at the Pediatric Allergy and Immunology Clinic, Children's Hospital, Ain Shams University during the period from December 2018 to April 2019. We enrolled 52 asthmatic children with concomitant allergic rhinitis sampled in a consecutive manner. They were subjected to skin prick testing for timothy grass pollen, positive histamine control and negative control. Results The study revealed high frequency of timothy grass pollen(TGP) sensitization occurring in 60.3% of patients with concomitant allergic rhinitis .wheal diameters pointed to sensitization only rather than actual allergy to TGP. TGP sensitization showed no significant correlation to disease duration. Children with rhinosinsuitis had comparable rates of TGP sensitization to those without rhinosinsuitis. Conclusion It is concluded from our results that sensitization to timothy grass pollen (TGP) is common in allergic rhinitis. The findings are limited by the sample size and consecutive manner of sampling. Wider scale studies are needed to accurately evaluate the frequency of timothy grass pollen (TGP) sensitization in our country.

Viral infection and allergy – What equine immune responses can tell us about disease severity and protection

Horses have many naturally occurring diseases that mimic similar conditions in humans. The ability to conduct environmentally controlled experiments and induced disease studies in a genetically diverse host makes the horse a valuable intermediate model between mouse studies and human clinical trials. This review highlights important similarities in the immune landscape between horses and humans using current research on two equine diseases as examples. First, equine herpesvirus type 1 (EHV-1) infection initiates a series of innate inflammatory signals at its mucosal entry site in the upper respiratory tract. These inflammatory markers are highly synchronized and predictable between individuals during viral respiratory infection and ultimately lead to adaptive immune induction and protection. The timing of early inflammatory signals, followed by specific adaptive immune markers correlating with immunity and protection, allow accurate outbreak tracking and also provide a foundation for understanding the importance of local mucosal immunity during other viral respiratory infections. Second, rare peripheral blood immune cells that promote allergic inflammation can be analyzed during Culicoides hypersensitivity, a naturally occurring type I IgE-mediated allergic disease of horses. Rare immune cells, such as IgE-binding monocytes or basophils, can be studied repeatedly in the horse model to unravel their larger mechanistic role in inflammation during allergic and other inflammatory diseases. We conclude with a survey of all other common equine inflammatory conditions. Together, this review serves as a reference and rationale for the horse as a non-rodent model for immunological research.

Think Twice before Interpreting the Skin Prick Test as Age, Body Mass Index, and Atopy Affect Reaction Time and Size

Introduction: The skin prick test (SPT) is a reliable method to confirm sensitization in IgE-mediated allergic diseases; however, it has been reported to be affected by several personal and environmental factors. Our objective was to determine the factors affecting the skin reactivity to histamine and allergens and investigate whether it differs according to age in terms of reading time. Methods: A total of 500 patients, aged 4 months–18 years, were enrolled in the study. Wheal and flare reaction sizes were documented as the mean of the longest and the midpoint perpendicular diameter in the 5th, 10th, 15th, and 20th min. Skin reactivity was compared between children >24 and ≤24 months of age. Results: We found larger histamine and allergen wheal sizes in children >24 months than the ones ≤24 months of age (p < 0.001 and p = 0.007, respectively). The duration of maximum histamine reactivity was 15 min for children >24 months whereas 10 min for children ≤24 months of age. The number of children losing their histamine reactivity after 15 and 20 min was significantly higher in the smaller age-group. Multiple regression analysis revealed a larger histamine reactivity in children >24 months of age, having obesity, and having allergen sensitization (p = 0.002, p = 0.003, and p = 0.018, respectively). Conclusion: It seems more accurate to evaluate SPT after 10 min in children ≤24 months of age. Cutoff values and ideal measurement time according to individual factors such as age, body mass index, or atopy are needed.

Preventive Effect of Allergen Immunotherapy on Asthma and New Sensitizations

Allergen immunotherapy (AIT) is a disease-modifying treatment for some IgE-mediated allergic diseases with the potential to have important preventive effects. Children with allergic rhinitis have a high risk of developing asthma, and treating allergic rhinitis with AIT may interfere with disease progression and prevent onset of asthma. Although the evidence is limited due to relatively few and heterogeneous studies, data nevertheless suggest that AIT has a preventive effect on development of asthma especially in children with rhinitis due to grass pollen allergy. AIT may also affect the development of new sensitizations. Both the degree of sensitization and the specific sensitization pattern may influence future disease severity and development of comorbidities. Hitherto, the indication for AIT for prevention of development of asthma in grass/birch pollen allergic children has been the same as for treatment of allergic rhinitis. Probably, AIT should be applied in the early stage of the allergic disease to have the greatest preventive effect on disease progression. Consequently, in the future, the potential preventive effects should influence the timing of initiating AIT. The window of opportunity to prevent asthma may primarily exist in young children with mild symptoms and a low degree of sensitization.

Ten-year monitoring of sensitization to house dust mites

Statistical studies of patients' sensitization to allergens make it possible to form a general picture of sensitization for the whole country, help doctors to develop competent tactics for examining patients in the regions and can be used for the development of new formulations of allergy vaccines.Objective. To study the sensitization to inhalation allergens Dermatophagoides pteronyssinus (Der. p.) and Dermatophagoides farinaе (Der. f.) in Moscow and the Moscow region in 2010–2019 and to identify the structure, features and dynamic changes in sensitization to Der. p. and Der. f. based on the analysis of the allergosensitivity profile of patients with IgE-mediated allergic diseases (IgEA).Materials and methods. Blood serum samples of Moscow and the Moscow region residents with IgEA (n = 2849) were examined by RIDA AllergyScreen method in 2010–2019.Results. According to the results of the study spanning the last ten years, about 18–21% of patients with IgEA in Moscow and the Moscow region have sensitization to Der. p. and/or Der. f. There was a statistically significant decrease in sensitization to Der. p. from 2017 to 2019. House dust mites of the type Der. f. more often cause a higher level of sensitization compared to Der. p.Discussion. The data obtained indicate the change in the sensitization of patients to Pyroglyphidae, namely Der. p. against the background of changes in the housing acarocomplex of Moscow and the Moscow region. Features of protein molecules of these species of dust mites may contribute to their varying degrees of the impact on immunological reactivity in the population studied.Conclusions. The decrease in the prevalence of Der. p. is most likely accounted for the changes in the ecosystem of homes of residents of Moscow and the Moscow region.

Allergy vaccines for specific immunotherapy

Allergen-specific immunotherapy (ASIT) has been used for more than a hundred years to treat patients with IgEmediated allergic diseases. The most common allergens have been obtained using molecular cloning technology in the past two decades. To increase the safety of immunotherapy, a large group of genetically modified allergens with reduced allergenic activity was created. The mechanism of action of these therapeutic allergens differs from natural allergen extracts, and more research is needed to understand how desensitization occurs in each case. The objective of this review is to introduce readers to new therapeutic allergy vaccines and their structural modification features as well as immunological effects on the body. To achieve this objective, we have analyzed and systematized the experimental developments presented in the literature on the main directions of creating new allergy vaccines: hypoallergenic derivatives of recombinant allergens, T cell epitope-based allergy vaccines and B cell epitope-based allergy vaccines, DNA vaccines.Summing up the results of the research presented in the literature, it is necessary to note the high heterogeneity of designs used to achieve the high efficiency of the developed therapeutic allergens. All allergy vaccines presented in the review solve the tasks set by the researchers: in experimental animal models they induce immunogenicity or tolerance, in clinical trials they reduce the symptoms of allergic reactions. The the effectiveness of the proposed medicinal products is quite high but its evaluation requires further long-term preclinical and clinical trials to confirm the safety and harmlessness of the created allergy vaccines.

CpG Adjuvant in Allergen-Specific Immunotherapy: Finding the Sweet Spot for the Induction of Immune Tolerance.

Prevalence and incidence of IgE-mediated allergic diseases have increased over the past years in developed and developing countries. Allergen-specific immunotherapy (AIT) is currently the only curative treatment available for allergic diseases that has long-term efficacy. Although AIT has been proven successful as an immunomodulatory therapy since its beginnings, it still faces several unmet needs and challenges today. For instance, some patients can experience severe side effects, others are non-responders, and prolonged treatment schedules can lead to lack of patient adherence and therapy discontinuation. A common strategy to improve AIT relies on the use of adjuvants and immune modulators to boost its effects and improve its safety. Among the adjuvants tested for their clinical efficacy, CpG oligodeoxynucleotide (CpG-ODN) was investigated with limited success and without reaching phase III trials for clinical allergy treatment. However, recently discovered immune tolerance-promoting properties of CpG-ODN place this adjuvant again in a prominent position as an immune modulator for the treatment of allergic diseases. Indeed, it has been shown that the CpG-ODN dose and concentration are crucial in promoting immune regulation through the recruitment of pDCs. While low doses induce an inflammatory response, high doses of CpG-ODN trigger a tolerogenic response that can reverse a pre-established allergic milieu. Consistently, CpG-ODN has also been found to stimulate IL-10 producing B cells, so-called B regulatory cells (Bregs). Accordingly, CpG-ODN has shown its capacity to prevent and revert allergic reactions in several animal models showing its potential as both preventive and active treatment for IgE-mediated allergy. In this review, we describe how CpG-ODN-based therapies for allergic diseases, despite having shown limited success in the past, can still be exploited further as an adjuvant or immune modulator in the context of AIT and deserves additional attention. Here, we discuss the past and current knowledge, which highlights CpG-ODN as a potential adjuvant to be reevaluated for the enhancement of AIT when used in appropriate conditions and formulations.

Bacterial and Fungal Toll-Like Receptor Activation Elicits Type I IFN Responses in Mast Cells.

Next to their role in IgE-mediated allergic diseases and in promoting inflammation, mast cells also have antiinflammatory functions. They release pro- as well as antiinflammatory mediators, depending on the biological setting. Here we aimed to better understand the role of mast cells during the resolution phase of a local inflammation induced with the Toll-like receptor (TLR)-2 agonist zymosan. Multiple sequential immunohistology combined with a statistical neighborhood analysis showed that mast cells are located in a predominantly antiinflammatory microenvironment during resolution of inflammation and that mast cell-deficiency causes decreased efferocytosis in the resolution phase. Accordingly, FACS analysis showed decreased phagocytosis of zymosan and neutrophils by macrophages in mast cell-deficient mice. mRNA sequencing using zymosan-induced bone marrow-derived mast cells (BMMC) revealed a strong type I interferon (IFN) response, which is known to enhance phagocytosis by macrophages. Both, zymosan and lipopolysaccharides (LPS) induced IFN-β synthesis in BMMCs in similar amounts as in bone marrow derived macrophages. IFN-β was expressed by mast cells in paws from naïve mice and during zymosan-induced inflammation. As described for macrophages the release of type I IFNs from mast cells depended on TLR internalization and endosome acidification. In conclusion, mast cells are able to produce several mediators including IFN-β, which are alone or in combination with each other able to regulate the phagocytotic activity of macrophages during resolution of inflammation.