IgE-mediated Diseases Research Articles

A Review on Novel Therapeutic Modalities and Evidence-based Drug Treatments against Allergic Rhinitis.

Allergic rhinitis (AR) is an IgE-mediated atopic disease that occurs due to inhaled antigens in the immediate phase. Misdiagnosis, insufficient treatment, or no treatment at all are frequent problems associated with the widespread condition known as chronic allergic rhinitis. AR symptoms include runny, itchy, stuffy, and sneezing noses. Asthma and nasal polyps, for example, sometimes occur simultaneously in patients. In order for people living with AR to be as comfortable and productive as possible, treatment should center on reducing their symptoms. The online sources and literature, such as Pubmed, ScienceDirect, and Medline, were reviewed to gather information regarding therapeutic modalities of AR and evidence-based treatments for the disease as the objectives of the present study. An increasing number of people are suffering from AR, resulting in a heavy financial and medical burden on healthcare systems around the world. Undertreating AR frequently results in a decline in quality of life. Treatment compliance is a critical challenge in the administration of AR. Innovative therapies are needed for RA to provide patients with symptom alleviation that is less expensive, more effective, and longer duration of action. Evidence-based guidelines are helpful for managing AR illness. Treating AR according to evidence-based standards can help in disease management. AR treatment includes allergen avoidance, drug therapy, immunotherapy, patient education, and follow-up. However, AR treatment with intranasal corticosteroids is more popular. Hence, in this review article, treatment options for AR are discussed in depth. We also discussed the incidence, causes, and new treatments for this clinical condition.

AllergoOncology: Biomarkers and refined classification for research in the allergy and glioma nexus-A joint EAACI-EANO position paper.

Epidemiological studies have explored the relationship between allergic diseases and cancer risk or prognosis in AllergoOncology. Some studies suggest an inverse association, but uncertainties remain, including in IgE-mediated diseases and glioma. Allergic disease stems from a Th2-biased immune response to allergens in predisposed atopic individuals. Allergic disorders vary in phenotype, genotype and endotype, affecting their pathophysiology. Beyond clinical manifestation and commonly used clinical markers, there is ongoing research to identify novel biomarkers for allergy diagnosis, monitoring, severity assessment and treatment. Gliomas, the most common and diverse brain tumours, have in parallel undergone changes in classification over time, with specific molecular biomarkers defining glioma subtypes. Gliomas exhibit a complex tumour-immune interphase and distinct immune microenvironment features. Immunotherapy and targeted therapy hold promise for primary brain tumour treatment, but require more specific and effective approaches. Animal studies indicate allergic airway inflammation may delay glioma progression. This collaborative European Academy of Allergy and Clinical Immunology (EAACI) and European Association of Neuro-Oncology (EANO) Position Paper summarizes recent advances and emerging biomarkers for refined allergy and adult-type diffuse glioma classification to inform future epidemiological and clinical studies. Future research is needed to enhance our understanding of immune-glioma interactions to ultimately improve patient prognosis and survival.

The Occurrence of Atopy in Patients with Isolated Spontaneous Mast Cell (or Nonallergic) Angioedema.

Isolated mast cell angioedema (MC-AE) can be divided into allergic and nonallergic (spontaneous) forms. The former is often associated with food, Hymenoptera venoms or drug allergies. This study aimed to evaluate the relationship between the occurrence of atopic diseases and the risk of angioedema. A retrospective study analyzed 304 patients with confirmed MC-AE and 1066 controls. All were analyzed for allergic asthma (AA), atopic dermatitis (AD) and allergic rhinitis (AR) based on ICD-10 codes. In addition, total IgE and peripheral eosinophilia were calculated. The analyzed atopic diseases were more frequent in the group of patients diagnosed with MC-AE than in the controls: 78 (25.7%) vs. 173 (16.2%) for p < 0.01. Patients diagnosed with AD had a higher risk of MC-AE (hazard ratio (HR) = 1.48,) similar to those diagnosed with AR (HR = 1.51). However, in patients with two or three atopic comorbidities, the risk increased significantly to HR = 2.45 or HR = 4.1, respectively. There was a positive correlation between the serum total IgE concentration or eosinophilia and the risk of angioedema (p < 0.01). Patients with MC-AE had a more frequent occurrence of atopic diseases associated with inhalant allergies. This risk increased in patients with IgE-mediated polymorphic disease.

An optimized method for IgE-mediated degranulation of human lung mast cells.

Mast cells are critically involved in IgE-mediated diseases, e.g., allergies and asthma. Human mast cells are heterogeneous, and mast cells from different anatomical sites have been shown to respond differently to certain stimuli and drugs. The origin of the mast cells is therefore of importance when setting up a model system, and human lung mast cells are highly relevant cells to study in the context of asthma. We therefore set out to optimize a protocol of IgE-mediated activation of human lung mast cells. Human lung mast cells were extracted from lung tissue obtained from patients undergoing pulmonary resection by enzyme digestion and mechanical disruption followed by CD117 magnetic-activated cell sorting (MACS) enrichment. Different culturing media and conditions for the IgE-mediated degranulation were tested to obtain an optimized method. IgE crosslinking of human lung mast cells cultured in serum-free media gave a stronger response compared to cells cultured with 10% serum. The addition of stem cell factor (SCF) did not enhance the degranulation. However, when the cells were put in fresh serum-free media 30 minutes prior to the addition of anti-IgE antibodies, the cells responded more vigorously. Maximum degranulation was reached 10 minutes after the addition of anti-IgE. Both CD63 and CD164 were identified as stable markers for the detection of degranulated mast cells over time, while the staining with anti-CD107a and avidin started to decline 10 minutes after activation. The levels of CD203c and CD13 did not change in activated cells and therefore cannot be used as degranulation markers of human lung mast cells. For an optimal degranulation response, human lung mast cells should be cultured and activated in serum-free media. With this method, a very strong and consistent degranulation response with a low donor-to-donor variation is obtained. Therefore, this model is useful for further investigations of IgE-mediated mast cell activation and exploring drugs that target human lung mast cells, for instance, in the context of asthma.

Formononetin inhibits IgE by huPlasma/PBMCs and mast cells/basophil activation via JAK/STAT/PI3-Akt pathways.

Food allergy is a prevalent disease in the U.S., affecting nearly 30 million people. The primary management strategy for this condition is food avoidance, as limited treatment options are available. The elevation of pathologic IgE and over-reactive mast cells/basophils is a central factor in food allergy anaphylaxis. This study aims to comprehensively evaluate the potential therapeutic mechanisms of a small molecule compound called formononetin in regulating IgE and mast cell activation. In this study, we determined the inhibitory effect of formononetin on the production of human IgE from peripheral blood mononuclear cells of food-allergic patients using ELISA. We also measured formononetin's effect on preventing mast cell degranulation in RBL-2H3 and KU812 cells using beta-hexosaminidase assay. To identify potential targets of formononetin in IgE-mediated diseases, mast cell disorders, and food allergies, we utilized computational modeling to analyze mechanistic targets of formononetin from various databases, including SEA, Swiss Target Prediction, PubChem, Gene Cards, and Mala Cards. We generated a KEGG pathway, Gene Ontology, and Compound Target Pathway Disease Network using these targets. Finally, we used qRT-PCR to measure the gene expression of selected targets in KU812 and U266 cell lines. Formononetin significantly decreased IgE production in IgE-producing human myeloma cells and PBMCs from food-allergic patients in a dose-dependent manner without cytotoxicity. Formononetin decreased beta-hexosaminidase release in RBL-2H3 cells and KU812 cells. Formononetin regulates 25 targets in food allergy, 51 in IgE diseases, and 19 in mast cell diseases. KEGG pathway and gene ontology analysis of targets showed that formononetin regulated disease pathways, primary immunodeficiency, Epstein-Barr Virus, and pathways in cancer. The biological processes regulated by formononetin include B cell proliferation, differentiation, immune response, and activation processes. Compound target pathway disease network identified NFKB1, NFKBIA, STAT1, STAT3, CCND1, TP53, TYK2, and CASP8 as the top targets regulated at a high degree by formononetin. TP53, STAT3, PTPRC, IL2, and CD19 were identified as the proteins mostly targeted by formononetin. qPCR validated genes of Formononetin molecular targets of IgE regulation in U266 cells and KU812 cells. In U266 cells, formononetin was found to significantly increase the gene expression of NFKBIA, TP53, and BCL-2 while decreasing the gene expression of BTK TYK, CASP8, STAT3, CCND1, STAT1, NFKB1, IL7R. In basophils KU812 cells, formononetin significantly increased the gene expression of NFKBIA, TP53, and BCL-2 while decreasing the gene expression of BTK, TYK, CASP8, STAT3, CCND1, STAT1, NFKB1, IL7R. These findings comprehensively present formononetin's mechanisms in regulating IgE production in plasma cells and degranulation in mast cells.

Cow's Milk Protein Allergy.

Cow's milk allergy refers to an immunological reaction to milk protein. It is one of the commonest food protein allergies with an estimated prevalence of 0.5% to 3% at 1 y of life. The disease may be IgE or non-IgE mediated or mixed with a wide range of symptoms often involving multiple organ systems. Gastrointestinal manifestations are common in non-IgE disease and may consist of enteropathy, proctocolitis, colic, reflux-like symptoms, constipation, enterocolitis syndrome and eosinophilic esophagitis. The gold standard for diagnosis remains a double-blind placebo-controlled oral challenge. Specific IgE and skin prick tests may predict severe and persistent disease, and aid in deciding on reintroduction or oral immunotherapy; however, they do not contribute to a definitive diagnosis as they indicate only sensitization. In practice, an elimination diet followed by open challenge under medical supervision is often used for diagnosis except when symptoms are severe such as anaphylaxis. Management consists of the elimination of the allergen with resolution of symptoms between 1-4 wk later depending on the type of allergy. Extensively hydrolyzed and Amino acid formulas are used to substitute milk in infants. Soy-based formulas are often utilized in resource-limited settings. Tolerance to the protein develops over time and periodic reintroduction should be attempted every six months after the initial one year of elimination diet. Oral immunotherapy is a newer treatment technique for IgE-mediated disease. There is no firm evidence on prevention apart from recommending breast feeding in early life along with initiating complementary feeding between 4-6 mo age.

Prevalence and burden of coconut allergy in the United States

BackgroundEpidemiologic data on coconut allergy remains sparse in the United States despite the labeling requirement by the Food Allergen Labeling and Consumer Protection Act for products containing coconut. ObjectiveTo provide current estimates of the prevalence, severity, determinants, and distribution of coconut allergy in the United States. MethodsA comprehensive food allergy prevalence survey was administered to a nationally representative, probability-based sample of US households between October 1, 2015 and September 30, 2016. Eligible respondents included adults who were able to complete self- and parent-proxy report surveys in English or Spanish by means of web or phone. ResultsUsing survey responses from 78,851 individuals, 0.39% (95% confidence interval [CI], 0.33-0.45) of the US general population were categorized as having convincing coconut allergy. Among children, 0.22% (95% CI, 0.16-0.30) were estimated to have coconut allergy compared with 0.43% (95% CI, 0.37-0.51) of adults, whereas only 0.12% (95% CI, 0.08-0.18) of these children and 0.20% (95% CI, 0.16-0.24) of adults with convincing immunoglobulin E (IgE)–mediated coconut allergy reported physician-confirmed diagnoses. A current epinephrine prescription was reported by 40.1% (95% CI, 33.3-47.4) of those with convincing coconut allergy. Reactions involving multiple organ systems were reported by 47.5% (95% CI, 40.1-54.9) of those with convincing coconut allergy. ConclusionRoughly 1 in 260 Americans report symptoms consistent with an IgE-mediated allergy to coconut, although fewer than half of these individuals report receiving a physician diagnosis. Our data indicate that most individuals with reported coconut allergy meeting symptom-based criteria for convincingly IgE-mediated disease have comorbid FAs, and for many patients, clinical management seems to be suboptimal.

Epigenome-wide DNA methylation association study of circulating IgE levels identifies novel targets for asthma

Identifying novel epigenetic signatures associated with serum immunoglobulin E (IgE) may improve our understanding of molecular mechanisms underlying asthma and IgE-mediated diseases. We performed an epigenome-wide association study using whole blood from Framingham Heart Study (FHS; n=3,471, 46% females) participants and validated results using the Childhood Asthma Management Program (CAMP; n=674, 39% females) and the Genetic Epidemiology of Asthma in Costa Rica Study (CRA; n=787, 41% females). Using the closest gene to each IgE-associated CpG, we highlighted biologically plausible pathways underlying IgE regulation and analyzed the transcription patterns linked to IgE-associated CpGs (expression quantitative trait methylation loci; eQTMs). Using prior UK Biobank summary data from genome-wide association studies of asthma and allergy, we performed Mendelian randomization (MR) for causal inference testing using the IgE-associated CpGs from FHS with methylation quantitative trait loci (mQTLs) as instrumental variables. We identified 490 statistically significant differentially methylated CpGs associated with IgE in FHS, of which 193 (39.3%) replicated in CAMP and CRA (FDR < 0.05). Gene ontology analysis revealed enrichment in pathways related to transcription factor binding, asthma, and other immunological processes. eQTM analysis identified 124 cis-eQTMs for 106 expressed genes (FDR < 0.05). MR in combination with drug-target analysis revealed CTSB and USP20 as putatively causal regulators of IgE levels (Bonferroni adjusted P<7.94E-04) that can be explored as potential therapeutic targets. By integrating eQTM and MR analyses in general and clinical asthma populations, our findings provide a deeper understanding of the multidimensional inter-relations of DNA methylation, gene expression, and IgE levels. US NIH/NHLBI grants: P01HL132825, K99HL159234. N01-HC-25195 and HHSN268201500001I.

Mechanism and clinical evidence of immunotherapy in allergic rhinitis.

Allergic rhinitis is a common upper airway disease caused by hypersensitivity to various aeroallergens. It causes increased inflammation throughout the body and may be complicated by other otolaryngological pathologies such as chronic hyperplastic eosinophilic sinusitis, nasal polyposis, and serous otitis media. Allergic rhinitis is an IgE-mediated disease and immunotherapy can be a possible approach for patients to limit the use of antihistamines and corticosteroids. There is evidence that allergen immunotherapy can prevent the development of new sensitizations and reduce the risk of later development of asthma in patients with allergic rhinitis. However, some patients do not benefit from this approach and the efficacy of immunotherapy in reducing the severity and relapse of symptoms is still a matter of debate. This review highlights new aspects of allergic rhinitis with a particular focus on the impact of sexual dimorphism on the disease manifestation and efficacy to the allergen specific immunotherapy.

Mechanisms of Allergen Immunotherapy and Potential Biomarkers for Clinical Evaluation.

Allergen-immunotherapy (AIT) is an efficacious and disease-modifying treatment option for IgE-mediated diseases. Among these allergic rhinitis, insect venom allergy, food allergy, and allergic asthma are the most common candidates for AIT. AIT gives rise to clinical immunotolerance which may last for years after the treatment cessation. Mechanisms of AIT include suppression of allergic inflammation in target tissues and stimulation of the production of blocking antibodies, especially IgG4 and IgA. These mechanisms are followed by a reduction of underlying allergen-specific Th2 cell-driven responses to the allergens. Tolerance induction takes place through the desensitization of effector cells and stimulation of regulatory T cells that show their effects by mechanisms involving cell-cell cross-talk, but also other mechanisms, e.g., by the production of immunomodulatory cytokines such as, e.g., IL-10 and TGF-beta. From a personalized medical perspective, there is a need for clinical biomarkers of value in selecting responders and optimizing patient care during AIT. Also, a deeper understanding of underlying mechanistic processes will improve AIT's future outcomes. In this paper, the current knowledge of mechanisms in AIT is reviewed with a special focus on biomarkers of this therapy.

Neuroimmunology of allergic rhinitis : Part1: Cellular and humoral basic principles

Allergic rhinitis (AR) is avery common disease with ahigh prevalence worldwide. It is an IgE-mediated type2 inflammatory disease following exposure to inhalant allergens. Amultitude of different neuropeptides including substanceP, vasoactive intestinal peptide (VIP), calcitonin gene-related peptide (CGRP), nerve growth factor (NGF), and neuromedinU (NMU) can be released via peripheral axon or central reflexes, interact with immune cells, and thus contribute to neurogenic inflammation which causes the nasal hyperreactivity (NHR) characteristic of AR. Independent production of neuroendocrine hormones and neuropeptides by immune cells has also been demonstrated. Neuro-immune cell units arise when immune and neuronal cells colocalize, for which typical anatomic regions are, e.g., the mast cell-nerve functional unit. The focus of this review is the elucidation of neuroimmune communication mechanisms in AR.

Multiplex Specific IgE Profiling in Neonatal Stool of Preterms Predicts IgE-Mediated Disease

Background: The natural history of immunoglobulin (Ig) E-mediated diseases in preterm infants is still elusive. We aimed at developing a non-invasive tool for detecting specific IgE (sIgE) and eosinophil-derived neurotoxin (EDN) in neonatal fecal samples and evaluating its predictive value for the development of IgE-mediated diseases during the first year of life. Methods: We developed a stool extraction protocol, followed by freeze-drying and solubilization. The sIgEs were investigated in neonatal fecal samples from 21 preterm infants with a 300-allergen multiplex and confirmed by a capillary Western blot with a nano-immunoassay. EDN concentration was used to investigate the local eosinophilic component. Results: The multiplexed allergen assay detected sIgE in all of the samples. A Western blot was used to confirm the results. The frequency and levels of sIgE in the neonatal fecal samples differed between the infants who developed IgE-mediated diseases and the controls. Allergen specificity was associated with the development of cow’s milk allergy (CMA) and asthma. The development of CMA was predicted by the sIgE response to milk proteins (sensitivity was 88%; specificity was 78%). The EDN levels predicted the development of IgE-mediated diseases (sensitivity was 100%; specificity was 75%). Conclusion: The non-invasive investigation of neonatal fecal sIgE is a promising tool for predicting the subsequent development of IgE-mediated diseases. Clinical Implications: The non-invasive sIgE and EDN profiling of neonatal fecal samples from preterm infants can predict the development of IgE-mediated diseases.

Formononetin isolated from Sophorae flavescentis inhibits B cell-IgE production by regulating ER-stress transcription factor XBP-1.

IgE plays an important pathologic role in most, if not all, allergic conditions. We previously showed that ASHMI (anti-asthma herbal medicine intervention) suppressed IgE production in murine models of asthma and in asthma subjects. However, the active compounds in ASHMI responsible for the IgE suppression are still unknown. We sought to identify the compound(s) in ASHMI that are responsible for IgE inhibition as well as investigate the mechanisms by which the identified compound(s) decreases IgE production. The compounds in Sophorae Flavescentis were separated using Column chromatography and preparative-HPLC. The separated compounds were identified using LC-MS and 1H-NMR. U266 cells, an IgE-producing plasma cell line, were cultured with various concentrations of identified compounds. The levels of IgE production by the U266 cell were measured by ELISA. Trypan blue exclusion was used to determine the cell viability. The gene expression of XBP-1 and IgE-heavy chain was determined by RT-PCR. A single compound identified as formononetin was isolated from Sophorae Flavescentis. Formononetin significantly and dose dependently decreased the IgE production in U266 cells across a concentration range of 2-20 µg/ml (p < 0.05-0.001 vs. untreated cells) with an IC50 value of 3.43 μg/ml. There was no cytotoxicity at any tested concentration. Formononetin significantly decreased XBP-1, and IgE-heavy chain gene expression compared with untreated cells (p < 0.001). Formononetin decreased IgE production in human B cell line U266 cells in a dose-dependent fashion through the regulation of XBP-1 ER transcription. Formononetin may be a potential therapy for allergic asthma and other IgE-mediated diseases.

Malaysian Society of Allergy and Immunology Consensus Statement on Sublingual Immunotherapy in Allergic Rhinitis.

Allergic rhinitis (AR) is an IgE-mediated inflammatory disease of the upper airway. AR affects the patients' quality of life, is a known risk factor for asthma and a socio-economic burden. Allergen-specific immunotherapy (AIT), comprising sublingual immunotherapy (SLIT) and subcutaneous immunotherapy (SCIT), involves administering increasing doses of the causative allergen to induce clinical and immunologic tolerance to the allergens. It is the only currently available treatment for AR that has been proven to induce disease-modifying effects (i.e., long-term remission of allergic symptoms or potential prevention of asthma and new sensitizations). Although AIT is conventionally recommended for patients who are non-responsive to symptom-relieving pharmacotherapy, it is presently recommended as a first-line treatment for patients with moderate to severe AR who prefer a treatment with the potential for long-term remission. In light of the relatively recent implementation of AIT in Malaysia, guidelines on its appropriate indication and application are important to attain optimal outcomes. This consensus statement was developed by an expert group formed by the Malaysian Society of Allergy and Immunology to provide evidence-based recommendations for the practice of AIT in Malaysia. Patient and product selection, choice of AIT, and strategy towards an effective treatment outcome in AIT are presented.

In Silico Comparative Exploration of Allergens of Periplaneta americana, Blattella germanica and Phoenix dactylifera for the Diagnosis of Patients Suffering from IgE-Mediated Allergic Respiratory Diseases.

The burden of allergic illnesses is continuously rising, and patient diagnosis is a significant problem because of how intricately hereditary and environmental variables interact. The past three to four decades have seen an outbreak of allergies in high-income countries. According to reports on the illness, asthma affects around 300 million individuals worldwide. Identifying clinically important allergens for the accurate classification of IgE-mediated allergy respiratory disease diagnosis would be beneficial for implementing standardized allergen-associated therapy. Therefore, the current study includes an in silico analysis to identify potential IgE-mediated allergens in date palms and cockroaches. Such an immunoinformatic approach aids the prioritization of allergens with probable involvement in IgE-mediated allergic respiratory diseases. Immunoglobulin E (IgE) was used for molecular dynamic simulations, antigen-antibody docking analyses, epitope identifications, and characterizations. The potential of these allergens (Per a7, Per a 1.0102, and Bla g 1.0101) in IgE-mediated allergic respiratory diseases was explored through the evaluation of physicochemical characteristics, interaction observations, docking, and molecular dynamics simulations for drug and vaccine development.

Early IgE production is associated with accumulation of CD11b+ classical dendritic cells and CD11b+CD11c- macrophages in subcutaneous adipose tissue

In view of increased incidence of IgE-mediated diseases in Russia and worldwide, the efforts of various research groups are focused on studying the mechanisms that trigger the process of switching B-lymphocytes to IgE synthesis upon human exposure to harmless allergens, including the role of various antigen-presenting cells (APCs) in this process. However, the role of distinct APCs upon long-term penetration of low antigen doses via the tissue barriers, is yet poorly understood, as well as specific features of these events upon entrance of the antigen through the subcutaneous adipose tissue which contains tissueassociated lymphoid clusters (TALC).The aim of this work was to determine the relationship between the local accumulation of various APCs in the subcutaneous adipose tissue and development of early IgE production in a clinically relevant experimental model of allergy with long-term administration of low allergen doses. In this experimental model, specific IgE synthesis is induced, with minimal concomitant IgG production, thus mimicking the situation observed in patients with clinically sound allergies. BALB/c mice were immunized for 4 weeks subcutaneously in the withers area or intraperitoneally with low (100 ng) or high (10 μg) doses of the model allergen (ovalbumin). Blood samples were taken weekly from mice for ELISA testing, to determine the production of specific antibodies. Provocation tests were performed with high dose of the allergen, and adipose tissue samples were taken from the site of antigen injection for flow cytometric assays, in order to evaluate the contents of various APC subpopulations. Specific IgE production was induced mainly by subcutaneous injection of the antigen at low doses (100 ng) into the area of withers. When using this experimental regimen, we observed accumulation of classical CD11b+ cells in adipose tissue at the withers site, but not in the peritoneal adipose tissue, in absence of CD11b- classical, inflammatory or plasmacytoid, dendritic cells. These findings coincided in time with increased production of specific IgE on days +14 to +21. Accumulation of CD11b+CD11c- macrophages and their CD206+ M2 subpopulations at early terms (days +7 and +21) was also observed only after subcutaneous injection of the antigen into the withers area. The high-dose antigen injection (10 μg) which mediated IgG1 production to greater extent than production of IgE, led to earlier accumulation of CD11b+ classical dendritic cells (on day 7th), and to the absence of macrophage accumulation at later stages (day 21th). Thus, the early start of specific IgE production upon low-dose injection of the antigen into the subcutaneous adipose tissue may be associated with its presentation by CD11b+ classical dendritic cells in the presence of CD11b+CD11c- macrophages.

Ligelizumab impairs IgE-binding to plasmacytoid dendritic cells more potently than omalizumab and restores IFN-α production and FOXP3+ Treg generation.

Ligelizumab is an anti-IgE monoclonal antibody binding IgE with higher affinity than omalizumab that is under clinical investigation for several IgE-mediated diseases. We previously showed that omalizumab removes IgE bound to FcεRI on plasmacytoid dendritic cells (pDCs) and restores their ability to produce IFN-α and regulatory T cells (Tregs). The aim of this work is to investigate the capacity of ligelizumab to regulate functional properties of pDCs in comparison with omalizumab. pDCs were isolated from atopic donors and IgE was detached from FcεRI on pDCs with designed ankyrin repeat protein (DARPin) bi53-79. pDCs were resensitized with IgE alone or in the presence of ligelizumab or omalizumab prior to IgE-FcεRI crosslinking and Toll-like receptor 9 (TLR9) stimulation. Flow cytometry, ELISA, coculture experiments and intranuclear staining were performed to determine cytokine production and Treg generation. An antigen-specific model of resensitization and IgE-crosslinking was also performed. The levels of serum total free IgE show a non-linear positive correlation with the frequency of IgE+ pDCs displaying IgE bound to FcεRI within the 43 individual donors included in the study. Ligelizumab displays stronger capacity than omalizumab to block the binding of free IgE to FcεRI on human pDCs, resulting in a greater restoration of TLR9-L-induced IFN-α production. Ligelizumab also restores the ability of pDCs to generate FOXP3+ Tregs as previously reported for omalizumab. The uncovered novel molecular mechanisms of ligelizumab to regulate functional properties of pDCs from atopic donors might have important clinical implications for anti-IgE treatments in different IgE-mediated diseases.

How the Immune System Responds to Allergy Immunotherapy.

IgE-mediated diseases represent a highly diversified and multifactorial group of disorders that can deeply impact the patients' quality of life. Currently, allergy immunotherapy (AIT) still remains the gold standard for the management of such pathologies. In this review, we comprehensively examine and discuss how AIT can affect both the innate and the adaptive immune responses at different cell levels and propose timing-scheduled alterations induced by AIT by hypothesizing five sequential phases: after the desensitization of effector non-lymphoid cells and a transient increase of IgE (phase 1), high doses of allergen given by AIT stimulate the shift from type 2/type 3 towards type 1 response (phase 2), which is progressively potentiated by the increase of IFN-γ that promotes the chronic activation of APCs, progressively leading to the hyperexpression of Notch1L (Delta4) and the secretion of IL-12 and IL-27, which are essential to activate IL-10 gene in Th1 and ILC1 cells. As consequence, an expansion of circulating memory Th1/Tr1 cells and ILC-reg characterizes the third phase addressed to antagonize/balance the excess of type 1 response (phase 3). The progressive increase of IL-10 triggers a number of regulatory circuits sustained by innate and adaptive immune cells and favoring T-cell tolerance (phase 4), which may also be maintained for a long period after AIT interruption (phase 5). Different administration approaches of AIT have shown a similar tailoring of the immune responses and can be monitored by timely, optimized biomarkers. The clinical failure of this treatment can occur, and many genetic/epigenetic polymorphisms/mutations involving several immunological mechanisms, such as the plasticity of immune responses and the induction/maintenance of regulatory circuits, have been described. The knowledge of how AIT can shape the immune system and its responses is a key tool to develop novel AIT strategies including the engineering of allergen or their epitopes. We now have the potential to understand the precise causes of AIT failure and to establish the best biomarkers of AIT efficacy in each phase of the treatment.

Omalizumab and allergen immunotherapy for respiratory allergies: A mini-review from the Allergen-Immunotherapy Committee of the Italian Society of Pediatric Allergy and Immunology (SIAIP).

Although currently approved to treat severe asthma and chronic spontaneous urticaria, omalizumab has also been an effective and safe add-on treatment for other allergic diseases. Namely, omalizumab has been proposed to be used as add-on therapy in patients with allergic rhinitis and asthma and undergoing specific allergen immunotherapy (AIT). AIT is the only treatment that modifies the natural history of IgE-mediated diseases. This brief review summarizes the available evidence and controversies on the efficacy and safety of omalizumab combined with specific AIT.

Dupilumab: Advances in the off-label usage of IL4/IL13 antagonist in dermatoses.

Type 2 immune response refers toa complicated series of immune responses characterized by Th2 polarization and Th2 cytokines secretion. The IgE secretion, airway hypersensitivity, and effector cell recruitment (eosinophils, mast cells, basophils) in skin lesion and peripheral blood stream could be upregulated during the activation of type 2 immune response. Th1/Th2 ratio, also referred as Th1/Th2 balance, represent the T lymphocytes immune pattern to a certain degree: Th1-dominated responses are often involved in intracellular infections (e.g., mycobacterium tuberculosis) and autoimmune diseases (e.g., Graves' disease) while Th2-dominated responses are involved in allergic conditions (e.g., atopic dermatitis, eczema), IgE mediated diseases (e.g., urticaria), and fibrotic dermatoses (e.g., keloids). Dupilumab, as one of the most widely applied Th2 cytokine inhibitors, could block the bioactivity of IL-14/IL-13 via competitively binding to the common IL-4Rα subunit shared by IL-4 and IL-13 receptors. In addition to the direct inhibition of type 2 response, dupilumab is also effective in autoimmune and some infectious skin diseases through indirect regulation of type 1 immune response. The pathological mechanism of Th2 responses and advanced clinical application of dupilumab in skin diseases will be summarized and discussed in the review.