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Isoglobotrihexosylceramide (iGb3), a well-characterized natural killer T cell ligand found in mammalian tissues, is also known as a glycosphingolipid that contains the human IgE epitope α-Gal (Galα1,3Gal) structure. Here, we analyzed the reactivity of several mice and human serum immunoglobulins against iGb3. Additionally, we isolated and characterized the variable region sequences of a monoclonal antibody that specifically recognizes iGb3. No IgE reactive with iGb3 was detected in sera from MRL/lpr mice, which are known to produce autoreactive antibodies, or in sera from healthy human donors. Furthermore, no induction of IgE and IgG was observed in the sera of mice immunized with iGb3; only IgM reactivity to iGb3 was detected. Further analysis of an anti-iGb3 monoclonal antibody generated from the splenocytes of an iGb3-immunized mouse revealed that the nucleotide sequences of the variable regions exhibited high homology to those of antibodies recognizing glycoconjugates containing Galα1,3 or Galα1,4 structures. These results indicate that the mouse genome harbors genes capable of encoding antibodies that recognize α-linked galactose-containing glycans, including iGb3, but that iGb3 is not sufficiently immunogenic to induce IgE in mammalian lymphocytes.

Background: The KIT receptor tyrosine kinase and its ligand, stem cell factor (SCF), control proliferation and survival of mast cells. Thus, targeting KIT signaling may show promise for the treatment of allergic diseases involving mast cells. Recently, we discovered a new compound, MOD000001, as a potential small-molecule KIT kinase inhibitor by using an in silico approach. Objective: We sought to determine whether MOD000001 is highly selective to KIT, inhibits KIT signaling in mast cells, and affects IgE-mediated mast cell activation. Methods: The interaction of MOD000001 with 468 human kinases and its inhibitory activity against KIT were profiled and evaluated by using KINOMEscan (Discover X/Eurofins Corporation, Fremont, Calif) and cell-free kinase assays, respectively. The effects of MOD000001 on SCF-dependent signaling were examined by using primary mouse and human mast cells. The effects of MOD000001 on SCF-induced degranulation and passive cutaneous anaphylaxis reaction were examined in mice. Results: MOD000001 interacted with KIT and inhibited KIT kinase activity with high selectivity. MOD000001 suppressed SCF-induced KIT signaling in mouse and human mast cells and in mice. Passive cutaneous anaphylaxis reaction was suppressed in mice treated with MOD000001 both for a short-term (1 week) and for a long-term (7 weeks). Mice treated with MOD000001 for a long-term, but not for a short-term, showed skin mast cell reduction. Conclusions: MOD000001 is a highly selective KIT inhibitor that can suppress IgE-mediated mast cell activation in vivo. MOD000001 may do so by reducing tissue mast cell numbers or by other unknown mechanisms. The findings suggest potential benefits of MOD000001 for allergic diseases involving IgE-mediated mast cell activation.

Background: Chronic Spontaneous Urticaria (CSU) is an immune-mediated skin disease that may require prolonged treatments. Currently, there are no recommendations for treatment discontinuation once CSU symptoms are controlled, particularly among patients primarily diagnosed with severe CSU. Objective: In this real-life study we aimed to describe our experience of omalizumab (Oma) treatment withdrawal in CSU and define biomarkers related to these outcomes. Methods: CSU patients followed at our allergy clinic from January 2016 to December 2022 were included. Response to Oma therapy, and Oma-withdrawal outcomes among patients who reached complete remission for >6 months were analyzed. Results: During the study period 192/335(%) CSU patients were categorized as severe-CSU and entitled to receive Oma according to our country's regulations. Of them, 131/192(68%) were considered “Oma-responders”, and 95/131(72.5%) patients underwent gradual treatment withdrawal. Successful Oma-withdrawal was documented in 47/95(49.5%) whereas 48/95(50.5%) patients experienced flare and were defined as unsuccessful OMA-withdrawal. The first was associated with shorter disease duration 7.1 ± 7.4 years vs. 10.7 ± 9.4 (P = 0.042), lower baseline-IgE 81.6 ± 84.1IU/ml vs. 324.7 ± 555.9 (P = 0.005), and lower baseline-eosinophils count 131.4 ± 110.5 vs. 195.6 ± 98.4 (P = 0.043) in comparison to failure of Oma-withdrawal group. Conclusion: OMA may be successfully withdrawn in up to 50% of severe CSU patients following complete remission of disease symptoms, utilizing a gradual withdrawal protocol. Oma-withdrawal failure was linked with longer duration of disease as well as high IgE and eosinophil counts prior to initiation of Oma therapy. These parameters may enable the design of a treatment withdrawal algorithm.

Background: The immunoglobulin E (IgE) response to Angiostrongylus cantonensis infection increases in the host. This study analyzed the IgG and IgE responses detected in different body fluids of A. cantonensis-infected mice. Methods: BALB/c (high susceptibility), CBA (medium), and C57BL/6 and C57BL/10 (resistance) strain mice were used in this study. The levels of IgM, IgG, and IgE in the serum and cerebrospinal fluid (CSF) from infected mice were compared. A. cantonensis-reactive antigens from BALB/c and C57BL/6 mice CSF were also analyzed. Results: Antibodies against fifth-stage larvae (L5) antigens increased in mice CSF, particularly IgE, relate to worm rejection and the susceptibility of different mouse strains. The increased IgE level in BALB/c mice CSF is lower than that from others, suggesting IgE response in brain is more important than that in serum. Anti-L5 and anti-excretory/secretory (ES) antigen IgE and IgG responses in CSF were analyzed. In addition, the antibody-dependent eosinophil-mediated cytotoxicity induced by anti-excretory/secretory (ES) antigen antibodies may be the reason of severe brain inflammation in infected BALB/c mice. IgE and IgG antibodies against a 105 kDa protein of L5 antigen was detected at week 3 post-infection in C57BL/6 mice and week 5 post-infection in BALB/c mice. We suggest that 105 kDa protein is related with the antibody response of A. cantonensis-infected mice. Conclusion: We found that IgE antibodies in mice CSF against L5 antigens related to worm rejection in mice brains. This study may help to identify specific angiostrongyliasis markers that can be applied for clinical diagnosis and treatment in future.

Poorly controlled asthma is especially common in low resource countries. Aside from lack of access to, or poor technique with, inhaled beta-2 agonists and corticosteroids, the most problematic forms of asthma are frequently associated with both fungal allergy and exposure, especially in adults leading to more asthma exacerbations and worse asthma. The umbrella term ‘fungal asthma’ describes many disorders linked to fungal exposure and/or allergy to fungi. One fungal asthma endotype, ABPA, is usually marked by a very high IgE and its differential diagnosis is reviewed. Both ABPA and fungal bronchitis in bronchiectasis are marked by thick excess airway mucus production. Dermatophyte skin infection can worsen asthma and eradication of the skin infection improves asthma. Exposure to fungi in the workplace, home and schools, often in damp or water-damaged buildings worsens asthma, and remediation improves symptom control and reduces exacerbations. Antifungal therapy is beneficial for fungal asthma as demonstrated in nine of 13 randomised controlled studies, reducing symptoms, corticosteroid need and exacerbations while improving lung function. Other useful therapies include azithromycin and some biologics approved for the treatment of severe asthma. If all individuals with poorly controlled and severe asthma could be ‘relieved’ of their fungal allergy and infection through antifungal therapy without systemic corticosteroids, the health benefits would be enormous and relatively inexpensive, improving the long term health of over 20 million adults and many children. Antifungal therapy carries some toxicity, drug interactions and triazole resistance risks, and data are incomplete. Here we summarise what is known and what remains uncertain about this complex topic.

Chronic spontaneous urticaria (CSU) is a common skin disease without an etiology in the vast majority of cases. The similarity of symptoms and pathology to allergen-induced skin reactions supports that skin mast cell IgE receptor activation is also involved in CSU. Accumulating evidence also supports a role for blood basophils in disease expression. Blood basopenia is noted in active CSU disease with the recruitment of blood basophils to skin lesion sites. Blood basophils further display altered IgE receptor mediated degranulation patterns in two phenotypes that improve in remission. In active CSU subjects, changes in IgE receptor signaling molecule expression levels accompany the altered degranulation function in blood basophils. The success of therapies targeting IgE in CSU patients have also shown that altered blood basophil phenotypes and enumeration have potential use as a disease biomarker.

The signs and symptoms of chronic urticaria (CU) are caused by the activation and degranulation of skin mast cells (MCs). Recent studies have added to our understanding of how and why skin MCs are involved and different in CU. Also, novel and relevant mechanisms of MC activation in CU have been identified and characterized. Finally, the use of MC-targeted and MC mediator-specific treatments has helped to better define the role of the skin environment, the contribution of specific MC mediators, and the relevance of MC crosstalk with other cells in the pathogenesis of CU. Here, we review these recent findings and their impact on our understanding of CU, with a focus on chronic spontaneous urticaria (CSU). Also, we highlight open questions, issues of controversy, and unmet needs, and we suggest what studies should be performed moving forward.

Background: Occupational exposure to wood dust, generated by various individual wood species, both softwood and hardwood, has been extensively documented as a causative factor for reduced lung function, frequent respiratory symptoms, and increased immunological responses in wood workers. This study explores the impact of wood dust from mixed tropical hardwood species on lung function, respiratory symptoms, and Immunoglobulin (Ig) E and G levels. Methods: A cross-sectional study was conducted among wood workers at the Accra Timber Market and a control group from the University of Ghana. Particulate matter (PM) was sampled using a Minivol Sampler set to a flow rate of 5 l/min. Respiratory symptoms were assessed using questions adapted from the British Medical Research Council (MRC) questionnaire (1960). Lung volumes and airflow rates were measured using a spirometer. Total serum IgE and IgG levels were quantified using ELISA. Results: No significant differences were observed between the wood workers and the controls for demographic variables. Wood workers exhibited a significantly higher prevalence of respiratory symptoms, particularly rhinitis, with many reporting the absence of symptoms during holidays. Lung function parameters (VC, FEV1, FEV1%, PEFR, and FEF25-75%) were significantly reduced (p

Background: Allergic parotitis (AP), due to its non-specific symptoms, frequently poses a diagnostic challenge, leading to cases being overlooked or misdiagnosed by clinicians. Objective: This study aimed to elucidate detailed clinical characteristics and common diagnostic indicators of AP. Methods: A comprehensive review and analysis of medical records was conducted from patients diagnosed with AP, encompassing demographic, clinical, and laboratory data, at the Affiliated Stomatological Hospital of Nanjing Medical University between January 2019 and March 2022. Results: The study enrolled 17 patients, evidenced by an average age of 36.00 ± 12.95 years. Common presentations of AP among the patients included notable symptoms such as parotid gland swelling, associated pain, and xerostomia. Ten patients had other atopic diseases. Palpation revealed the affected parotid glands to be soft and nodular, with an elevated local skin temperature. The unstimulated whole saliva flow rate was decreased. Ultrasonography demonstrated increased volume, reduced echo heterogeneity, and lymph node enlargement in the affected parotid glands. All cases observed increased serum salivary amylase and total IgE levels. Investigation of food allergens and inhaled allergen-specific IgE showed that all patients had suspected food allergies. Food provocation tests (FPT) induced AP in 13 cases, confirming the role of food allergens. Conclusion: Food allergens are involved in the etiology of AP, underscoring the importance of comprehensive clinical evaluation, including symptoms, signs, and confirmatory auxiliary tests, such as FPT, for accurate diagnosis and differentiation from other salivary gland pathologies.

Approximately 80% of the global cattle population is at risk of infestation and infection by ticks and tick-borne diseases (TTBDs). The economic losses from animal mortality, reduced production, vector control costs and animal treatment are very substantial, hence there is an urgent need to develop and deploy alternative vector control strategies. Breeding for host tick resistance has the potential for sustainable large-scale TTBD control especially in cattle. The gold standard method for phenotyping tick resistance in cattle is by counting ticks on the body but is very laborious and subjective. Better methods for phenotyping tick resistance more objectively, faster and at scale, are essential for selecting host genetic resistance to ticks. This study investigated the correlation between haematological cellular profiles and immunological responses (immunoglobulin E, IgE) and full body tick counts in herds of Bos indicus and Bos taurus following artificial tick challenge with Rhipicephalus decoloratus larvae. Fifty-four Friesian and Ayrshire (Bos taurus) and 52 East African Zebu (Bos indicus) calves were each infested with ∼2500 larvae. Near-replete adult female ticks (≥ 4.5 mm) were counted daily from Day 20–25. Blood and serum samples were obtained from each animal on Days 0 and 23 for cellular blood and IgE titre analysis, respectively. The indicine cattle were refractory to R. decoloratus infestation in comparison with the taurine breed (P

Summary: Background: Pancreatic ductal adenocarcinoma (PDAC) has a dismal prognosis and it is characterized by predominant pro-tumor Th2-type inflammation. T follicular helper (Tfh) cells are relevant immunoregulators in cancer, and often correlate with better survival. How the Th2-skewed microenvironment in PDAC modulates the differentiation of Tfh cells and their immunoregulatory function is unknown. Methods: We carried out high-dimensional flow cytometry and T-cell receptor- and RNA-sequencing, as well as bioinformatics, immunohistochemistry and in vitro mechanistic studies. Findings: We identified Tfh1-, Tfh2-, and Tfh17-like cell clusters in the blood, tumors and tumor-draining lymph-nodes (TDLNs) of chemo-naïve PDAC patients and showed that high percentages of Tfh2 cells within the tumor tissue and TDLNs correlated with reduced patient survival. Moreover, only Tfh2 cells were highly activated and were reduced in frequency in patients who responded to neoadjuvant chemotherapy. RNA-sequencing analysis of immunoglobulin expression showed that tumor and TDLN samples expressed all immunoglobulin (IGH) isotypes apart from IGHE. Consistent with these findings, Tfh2 cells differentiated in vitro by tumor microenvironment-conditioned dendritic cells promoted the production of anti-inflammatory IgG4 antibodies by co-cultured B cells, dependent on IL-13. Moreover, unexpectedly, Tfh2 cells inhibited the secretion of pro-inflammatory IgE, dependent on prostaglandin E2. Interpretation: Our results indicate that in PDAC, highly activated pro-tumor Tfh2 favor anti-inflammatory IgG4 production, while inhibit pro-inflammatory IgE. Thus, targeting the circuits that drive Tfh2 cells, in combination with chemotherapy, may re-establish beneficial anti-tumor Tfh–B cell interactions and facilitate more effective treatment. Funding: Research grants from the Italian Association for Cancer Research (AIRC) IG-19119 to MPP and the AIRC Special Program in Metastatic disease: the key unmet need in oncology, 5 per Mille no. 22737 to CB, MF, CD, MR and MPP; the ERA-NET EuroNanoMed III (a collaborative european grant financed by the Italian Ministry of Health, Italy) project PANIPAC (JTC2018/041) to MPP; the Fondazione Valsecchi to SC.

Background: The incidence of tree nut allergies in children is increasing, with walnut allergy being the most common in the United States and Japan. Allergic reactions, including anaphylaxis, frequently occur at the first intake of tree nuts, suggesting prior sensitization. Objective: Our aim was to identify which children should be considered for workup for preexisting sensitization. Methods: Juglans regia (Jug r) 1–specific IgE screening for 0- to 35-month-old children who had a positive specific IgE result for egg white, milk, or wheat and had never ingested walnuts was conducted at a food allergy referral hospital between November 2018 and December 2022. Clinical data regarding age; sex; allergic disease complications; and egg, milk, or wheat allergy were examined retrospectively. Results: The rate of Jug r 1–specific IgE positivity (level > 0.34 kUA/L) of 205 children (125 of whom were boys) was 9.8%, with a median Jug r 1–specific IgE level of 12.5 kUA/L in patients with a positive test result. Eczema was observed in 119 patients (58%). The rate of Jug r 1–specific IgE positivity was significantly higher in the eczema-positive group (15.1% [18 of 119]) than in the eczema-negative group (2.3% [2 of 86]) (P = .002). In the eczema-positive group, the rates of Jug r 1–specific IgE positivity per sensitized antigen were 13.7% for egg, 17.0% for milk, and 17.1% for wheat. The rate of Jug r 1–specific IgE positivity was significantly higher in the group with severe eczema (26.6% [17 of 64]) than in the group with nonsevere eczema (1.8% [1 of 55]) (P < .001). Conclusion: Even in children younger than 3 years, 15% of children with eczema and egg, milk, or wheat sensitization were sensitized to Jug r 1.

Background: Mechanisms triggering the pathogenesis of chronic spontaneous urticaria (CSU) have been identified as type I autoallergic (which is associated with IgE antibodies against autoantigens) and type IIb autoimmune (which is driven by autoantibodies to FceR1 and/or IgE). Objective: Our aim was to define presumptive endotypes in patients with CSU by using tests amenable to use in routine clinical practice. Methods: A retrospective analysis of the medical records of 394 patients with CSU with or without chronic inducible urticaria or angioedema was performed. Patients were assigned to 1 of 4 groups as follows: (1) type I endotype of CSU, if they presented at least 1 of the following: allergic disease, total IgE level of at least 40UI/mL, and positive result of skin tests to inhalant allergen(s), (2) type IIb endotype of CSU, if they presented at least 1 of following: autoimmune disease, low total IgE level less than 40 IU/mL, positive autologous serum skin test result, positive for antinuclear antibodies in a titer of at least 1:160, and elevated level of anti–thyroid peroxidase, (3) overlap of type I/type IIb endotypes of CSU, if they presented with at least 1 marker of both type I and type IIb, and (4) non–type I/type IIb endotype of CSU, if they presented with none of the markers of type I or type IIb. Results: The mean age at onset of symptoms was 34 years; 82.2% of those with CSU were female, and angioedema and chronic inducible urticaria were found in 74.8% and 31.9% of patients, respectively. Of the patients with CSU, 38% presented with the type I endotype and 51% presented with type I/type IIb overlap, whereas 9% presented with the type IIb endotype and 2% presented with the non–type I/type IIb endotype. Eosinopenia was associated with type IIb and type I/type IIb overlap as opposed to the type I and non–type I/type IIb endotypes (P = .02). Conclusions: Most patients with CSU presented with features of the type 1 (autoallergic) endotype, whether associated with type IIb (autoimmune) endotype or not.

Resumen: El asma grave afecta del 3 al 10% de la población mundial, según estimaciones de la Iniciativa Global para el ASMA (GINA). El asma alérgica es uno de los fenotipos más comunes del asma grave y se caracteriza por una inflamación de tipo 2 provocada por alérgenos y en el que la inmunoglobulina E (IgE) es una mediadora clave, lo que la ha convertido en una diana terapéutica importante. La introducción de las terapias o de los tratamientos biológicos dirigidos ha supuesto la entrada del manejo del asma grave en la era de la medicina de precisión y que el objetivo del tratamiento aspirase a la remisión clínica de la enfermedad. Existe un porcentaje importante de pacientes con asma alérgica grave que no responden a los tratamientos y cuyos síntomas no están controlados. En este documento, un grupo de expertos en el manejo del asma alérgica grave ha revisado y evaluado la evidencia más relevante relativa a la fisiopatología y a los fenotipos del asma grave alérgica, la función de la IgE en la inflamación alérgica, la identificación de alérgenos, las técnicas, biomarcadores y retos diagnósticos y los tratamientos y estrategias disponibles para el manejo de la enfermedad, con un especial foco en los tratamientos biológicos. A partir de esta revisión se han desarrollado unas recomendaciones que han sido validadas a través de un proceso de consenso Delphi con el objetivo de ofrecer mejoras en el manejo del asma alérgica grave a los profesionales implicados e identificar las necesidades no cubiertas en el manejo de esta patología. Abstract: Severe asthma affects 3%-10% of the world's population, according to estimates by the Global Initiative for ASTHMA (GINA). Allergic asthma is one of the most common phenotypes of severe asthma and it is characterized by allergen-induced type 2 inflammation in which immunoglobulin E (IgE) is a key mediator, making it an important therapeutic target. The introduction of targeted biological therapies or treatments has entered the management for severe asthma in the era of precision medicine, and the goal of treatment is clinical remission of the disease. There is a significant percentage of patients with severe allergic asthma who do not respond to treatments and whose symptoms are not controlled. In this paper, a group of experts in the management of severe allergic asthma reviewed and evaluated the most relevant evidence regarding the pathophysiology and phenotypes of severe allergic asthma, the role of IgE in allergic inflammation, allergen identification, techniques, biomarkers and diagnostic challenges, available treatments and strategies for disease management, with a special focus on biological treatments. From this review, recommendations were developed and validated through a Delphi consensus process with the aim of offering improvements in the management of severe allergic asthma to the professionals involved and identifying the unmet needs in the management of this pathology.

Background: Few studies address the dynamic changes of body mass index (BMI) Z-scores during infancy with breastfeeding and their impact on childhood atopic diseases. Methods: A total of 183 children from a birth cohort regularly followed-up for 4 years were enrolled in this study. Time series data of BMI Z-scores from 1 month to 2 years of age was clustered using K-means method in R software. Breastfeeding status during the first 6 months of life was recorded and classified. The total serum and specific immunoglobulin E (IgE) levels to food and inhalant allergens were measured at age 0.5, 1, 1.5, and 2 years. Results: Using K-means clustering, the dynamic changes in BMI Z-scores were classified into three clusters (cluster A, increasing, n = 62; cluster B; decreasing, n = 62; cluster C, constant low, n = 59). Despite having no statistical association with atopic diseases, a decreasing trend in infantile BMI Z-scores was significantly associated with a higher prevalence of IgE sensitization at age 1 which increased the risk of rhinitis development at age 4 (P = 0.007). No difference in BMI Z-scores was determined between different breastfeeding patterns. However, exclusive formula feeding ≥6 months was found to be significantly associated with mite sensitization at age 1.5 years which risks asthma development at age 4 (P = 0.001). Conclusions: A decreasing trend of BMI Z-scores during infancy is determined to be inversely associated with IgE and allergen sensitization, which may potentially increase the risk of allergies in early childhood.

Mast cell activation is crucial to the development of allergic disease. New studies have shown that both IgE-dependent and -independent mast cell activation is temporally regulated by the circadian clock, a time-of-day-keeping system that consists of transcriptional-translational feedback loops of several clock genes. For instance, the core clock gene Clock controls the expression of the high-affinity IgE receptor (FcεRI) and interleukin-33 (IL-33) receptor ST2 on mast cells in a time-dependent manner. As a result, the threshold of IgE-dependent or IL-33-dependent mast cell activation differs between daytime and nighttime. This mechanism may underlie the observation that allergic disease shows a marked day–night change in symptom occurrence and severity. Consistent with this novel concept, environmental and lifestyle factors that disturb the normal rhythmicity of the circadian clock, such as irregular eating habits, can lead to the loss of circadian control of mast cell activation. Consequently, the degree of mast cell activation becomes equally strong at all times of day, which might clinically result in worsening allergic symptoms. Therefore, further understanding of the association between mast cell activation and the circadian clock is important to better manage patients with allergic disease in the real world, characterized by a “24/7 society” filled with environmental and lifestyle factors that disturb the circadian clock rhythmicity.

Summary: Background: Identifying novel epigenetic signatures associated with serum immunoglobulin E (IgE) may improve our understanding of molecular mechanisms underlying asthma and IgE-mediated diseases. Methods: 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. Findings: 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

This research investigated the effect of organic extracts from Litsea glutinosa (Lour.) C. B. Rob bark and its five heterocyclic compounds on induced diarrheal models. The bark of L. glutinosa was extracted with chloroform, ethyl acetate, and methanol. The resultant extracts were examined for disc-diffusion-guided activity against diarrhea-causing bacteria and chemical-induced anti-diarrheal properties in castor oil- and magnesium sulfate-induced diarrheal models. The effect of the extracts on gastrointestinal motility was tested in activated charcoal meal and barium sulfate milk models. The effects of the extracts on electrolytes (Na+, K+, Cl- and HCO3–), creatinine, triglycerides (TG), C-reactive protein (CRP), and immunoglobulin E (IgE) were assessed in the blood serum of treated animals. From the GC–MS analysis of the L. glutinosa methanol extract, five heterocyclic compounds were selected, and their interactions with target receptors were investigated using molecular docking techniques. The methanol extract (MExLG) showed the highest zone of inhibition for Shigella dysentriae (ZOI, 24 ± 0.9 mm) and E. coli (ZOI, 16.00 ± 1.14 mm), Salmonella paratyphi (18.23 ± 3.06 mm) and Vibrio cholerae (22.10 ± 2.62 mm). For both castor oil- and barium sulfate-induced diarrhea, MExLG achieved the highest levels of diarrheal inhibition 82.5% and 77.33%, respectively. MExLG showed the best in Na+, K+, Cl-, and HCO3– equivalence. Serum creatinine, TG, CRP and IgE levels were significantly (P

Background: Allergen-specific immunoglobulins have a crucial role in allergic diseases. Most wheeze episodes develop before school age, and allergic rhinitis later develops during early elementary school years. However, the clinical background and cytokine/chemokine profiles associated with changes in immunoglobulins during early school-age are poorly understood. Methods: This study used blood samples from children participating in the JECS Pilot Study. We examined nineteen kinds of aeroallergen-specific immunoglobulins (IgE, IgG1, IgG4, and IgA) levels in patients at age 6 and age 8. Fluctuations of Der f 1- and Cry j 1-specific immunoglobulins levels during the two periods were compared to assess the frequency of allergic statuses and clusters of cytokine/chemokine profiles. Results: The medians of aeroallergen-specific IgE levels did not fluctuate, and almost all IgG1 and IgG4 decreased. In IgA, four (e.g., Der f 1) increased, whereas the other four (e.g., Cry j 1) decreased. The ratio of the Der f 1-specific IgG1 level at age 8 to that at age 6 was higher in children with poor asthma control than in children with better asthma control. Moreover, the cytokine/chemokine cluster with relatively lower IL-33 and higher CXCL7/NAP2 was associated with lower Der f 1- and Cry j 1-specific IgG4 levels, but not IgE levels. Conclusions: The cluster of cytokine/chemokine profiles characterized by lower IL-33 and higher CXCL7/NAP2 was associated with the maintenance of aeroallergen-specific IgG4 levels. This result provides a basis for considering the control of aeroallergen-specific immunoglobulins.

α-Gal syndrome (AGS) is an allergy to meat and other products derived from non-primate mammals resulting from development of IgE antibodies against the oligosaccharide galactose-α,1,3-galactose (α-Gal). Sensitivity to α-Gal is linked to tick bites, particularly bites from Amblyomma americanum (lone star tick). Recent studies demonstrate early failure of bioprosthetic valves in the setting of chronic inflammation following exposure to animal-derived surgical implants. We report a case of AGS associated with restenosis of prior bovine pericardium used for a common femoral patch angioplasty requiring reoperation.

Vernal keratoconjunctivitis (VKC) is a severe ocular allergic disease characterized by chronic inflammation of the cornea and conjunctiva that may lead to loss of visual acuity and blindness. The disease occurs primarily in children and is more common in geographical regions characterized by warm temperatures and high humidity. The clinical manifestations of VKC, when inadequately treated, may lead to severe complications and corneal damage. The prevalence of allergen sensitization, specific serum immunoglobulin E (IgE), and specific tear IgE was reported in approximately 55%–60% of patients with VKC, confirming the involvement of IgE-mediated and non−IgE-mediated mechanisms in the pathophysiology of the condition. This article explores current knowledge on the immunological pathways of VKC and the role of the monoclonal anti-IgE antibody, omalizumab, in its management. The review evaluated the effects of omalizumab beyond the direct IgE-mediated reactions and discusses its potential as a therapeutic target for VKC. Multiple retrospective analyses, case series, and case reports have reported the effectiveness of omalizumab in the management of VKC. A summary of the clinical data from these studies revealed that in children with VKC omalizumab treatment was well tolerated with improvement or resolution of ocular symptoms, reduction in steroid use, and enhancement of quality of life. Omalizumab may serve as a promising treatment option for VKC due to its ability to target both IgE-mediated and non−IgE-mediated pathophysiological pathways. Larger, controlled clinical trials are needed to support these findings.

Immunoglobulin G4-related disease (IgG4-RD) is a chronic multi-organic immune fibrosing disease. It affects preferentially men around middle age and almost any organs can be involved; however, lymph nodes, submandibular and lacrimal glands, pancreas, and retroperitoneum are the most affected. The mainstay treatment is corticosteroids, sometimes adjuncts with DMARDs or rituximab as steroid sparing agents. Th2 inflammation is implicated in the pathophysiology of the disease. Several reports indicate that allergy and/or atopy often affect patients with IgG4-RD. The frequency varies greatly between studies with allergies/allergic diseases reported in 18–76% while atopy is reported in 14–46%. In studies including both, they affect 42 and 62% of patients. Rhinitis and asthma are the most frequent allergic diseases. IgE and blood eosinophiles are often elevated and few studies report that basophils and mast cells could participate in the disease pathogenesis; however, the implication of allergy and atopy remain unclear. No common allergen has been identified and IgG4 production seems to be polyclonal. Although a direct causal effect is unlikely, they could potentially shape the clinical phenotype. Allergies/allergic diseases and/or atopy are reported to be more frequent in IgG4-RD patients presenting head, neck, and thoracic involvement, with higher IgE and eosinophils and less frequent in retroperitoneal fibrosis; however, studies regarding allergy and atopy in IgG4-RD are highly heterogenous. The aim of this article is to review what is currently known about the allergy and atopy in the context of Ig4-RD.

Background/purpose: Exfoliative cheilitis (EC) is a chronic and reversible inflammatory disease of the lips without definite etiology. Clinically, different types of allergens can be found in exfoliative cheilitis patients, however, few studies have focused on the relationship between exfoliative cheilitis and hypersensitivity. This research aimed to investigate the prevalence of hypersensitivity in EC patients. Materials and methods: A prospective study was conducted in 30 patients with exfoliative cheilitis and 30 healthy controls, matched in age and sex. Laboratory tests included serum total IgE, allergen-specific IgE, and food-specific IgG. Results: Increased serum total IgE level, positive food-specific IgG were seen more frequently in exfoliative cheilitis patients than in healthy control (P

In the last decade, research has clarified the binding interactions between immunoglobulin E (IgE) and its high-affinity receptor, the FcεRI alpha chain (FcεRI). The formation of the IgE-FcεRI complex is crucial in the context of atopic allergies, linking allergen recognition to cellular activation and disease manifestation. Consequently, pharmacological strategies that disrupt these interactions are vital for managing atopic conditions. Historically, the complexity of the IgE-FcεRI binding process and challenges in producing functional recombinant derivatives has complicated data interpretation. However, advancements in structural biology, protein engineering, and immunological studies have enhanced our understanding of these protein-protein interactions (PPI), facilitating the development of more effective therapies. The introduction of anti-IgE therapies underscores the significance of the IgE-FcεRI PPI in allergic asthma. IgE, that is present locally and systemically, serves as a sensory mechanism in the adaptive immune response, particularly in mast cells (MCs) and basophils. When bound to FcεRI, IgE enables rapid memory responses to allergens, but dysregulation can lead to severe allergic asthma. Thus, the reactivity of IgE sensors can be finely modulated using various IgE-associated molecules. This review explores the mechanisms underlying IgE-dependent MC activation and its regulation by these molecules, including the latest therapeutic candidates under investigation., Competing Interests: Declaration of competing interest The authors declare no conflicts of interest., (Copyright © 2024 Elsevier B.V. All rights reserved.)

IgE antibodies raised against innocuous environmental antigens cause allergic diseases like allergic rhinitis, food allergy, and allergic asthma. While some allergies are often outgrown, others (peanut, shellfish, tree nut) are lifelong in the majority of individuals. Lifelong allergies are the result of persistent production of allergen-specific IgE. However, IgE antibodies and the plasma cells that secrete them tend to be short-lived. Persistent allergen-specific IgE titres are thought to be derived from the continued renewal of IgE plasma cells from memory B cells in response to allergen encounters. The initial generation of allergen-specific IgE is driven by B cell activation by IL-4 producing Tfh cells, but the cellular and molecular mechanisms of the long-term production of IgE are poorly characterized. This review investigates the mechanisms governing IgE production and Tfh activation in the primary and recall responses, towards the objective of identifying molecular targets for therapeutic intervention that durably inactivate the IgE recall response., Competing Interests: Conflict of interest The author receives funding from ALK Abello A/S., (Crown Copyright © 2024. Published by Elsevier B.V. All rights reserved.)

Background: Mast cells are key effector cells that elicit immunoglobulin E (IgE)-mediated allergic inflammations. Allergen cross-linking of IgE bound to the high-affinity IgE receptor, FcεRI, on mast cells triggers signaling cascades that activate signal proteins and evoke extracellular Ca 2+ influx, which are crucial for cytokine production. The β2-adrenergic receptor (Adrb2) on mast cells negatively regulates FcεRI signaling, as demonstrated by the inhibition of IgE/antigen (Ag)-induced activation by Adrb2 agonists., Objective: Although β2-adrenergic-related reagents are known to influence mast cell functions, the specific intrinsic role of Adrb2 in these cells is not fully understood, potentially because of off-target effects. In this study, the additional roles of Adrb2 in mast cells were investigated, specifically the involvement of Adrb2 in FcεRI signaling, using Adrb2 -/- mice., Methods: Adrb2 -/- mice were used to investigate the roles of Adrb2 in mast cells by examining bone marrow-derived mast cells (BMMCs) for surface expression of mast cell markers, granule numbers, and gene expression of mast cell proteases. Cytokine production, Ca 2+ influx, and nuclear factor of activated T cells (NFAT) nuclear translocation were measured in Adrb2 -/- and Adrb2 +/+ BMMCs upon IgE/Ag stimulation., Results: Adrb2 -/- did not affect the generation of BMMCs, their surface expression of mast cell markers, granule numbers, or gene expression of mast cell proteases, indicating that the absence of Adrb2 had no adverse effect on mast cell development. However, Adrb2 -/- BMMCs exhibited reduced tumor necrosis factor α (TNFα) production and diminished Ca 2 ⁺ influx upon IgE/Ag stimulation, which correlated with decreased NFAT translocation. Restoration of Adrb2 in Adrb2 -/- BMMCs rescued cytokine production. Notably, FcεRI-mediated phosphorylation of the phospholipase PLCγ1 and mitogen-activated protein kinases (MAPKs) remained unchanged in the absence of Adrb2., Conclusion: These results suggest that Adrb2 has a novel ligand-independent function, increasing Ca 2+ entry in mast cells when stimulated with IgE/Ag., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Allergen-specific antibodies (Abs), IgE, and IgG4 increase during the early phase of oral immunotherapy (OIT) of allergen food in patients; subsequently, IgE levels decrease and specific IgG4 levels increase after successful OIT treatment. The detailed profile of these Abs during OIT remains largely unclear. We developed a diagnostic tool to assess the OIT efficacy and extent of responsiveness based on a profiling method by identifying epitopes recognized by the Ab classes of IgE or IgG4. A peptide microarray followed by microplate analysis using synthetic peptides was used to identify 14 epitopes widely recognized by IgE and/or IgG4 in the serum samples of patients with OIT among the amino acid sequences of five major cow's milk allergens. The set of defined 14 epitopes clarified different epitope profiles of allergen-specific IgE and IgG4 in each patient's serum samples. Moreover, the total signal of Abs recognizing all 14 epitopes was equal to the sum of all individual epitope-specific Abs. It was further observed that the quantitative value of IgE concentrations of 14 epitopes-ALL correlated with the ImmunoCAP IgE value. These findings strongly imply that the quantity of IgE and IgG4 recognizing epitopes-ALL may easily be used to measure allergy severity. To investigate this potential, we developed an immunochromatographic method that can detect IgE and IgG4 levels in patient samples. This study clearly demonstrated the usefulness of the defined 14 epitopes and their mixture, "epitopes-ALL," and that the simple and reliable methods of immunochromatography and microplate analyses demonstrating the epitope profile of allergen-specific Abs are applicable for diagnostic use at multiple disease stages and the OIT-treatment course in patients with cow's milk allergy., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024. Published by Elsevier B.V.)

Background: During the active phase of urticaria, a decrease in peripheral blood basophils, known as basopenia, is observed. We previously reported that basopenia occurs as a result of basophils migrating to the skin in a contact dermatitis model where a Th2 response is induced with oxazolone., Objective: Although there is currently no established model for urticaria, given that urticaria is an IgE-mediated immediate-type allergic reaction, we aimed to determine whether an IgE-mediated model could reproduce the decrease in basophils in peripheral blood observed during the active phase of urticaria., Methods: Mice were pretreated with 2,4,6-trinitrophenylhaptene (TNP)-specific IgE and basophil dynamics were examined following stimulation with TNP-ovalbumin. Mast cell-deficient WBB6F1-Kit W /Kit W-v mice were used to investigate the role of mast cells in this IgE-mediated model., Results: Following stimulation, we observed immediate ear swelling and basopenia after 0.5 hours. However, the number of basophils observed in the skin lesions was low, while a higher number of basophils were observed in the antigen-draining lymph nodes (LN). In mast cell-deficient mice, no increase in basophils in the LN was observed, reflecting reduced antigen influx into the LN, but basophils remained in the skin., Conclusions: In the IgE-mediated mouse model, basopenia was observed, which coincided with the induction of inflammation in the skin. The migration of basophils to the LN in this model suggests that the systemic immune system, including the LN, should be considered when exploring the pathogenesis of urticaria in humans., Competing Interests: Declaration of Competing Interest The authors have no conflict of interest to declare, (Copyright © 2024 Japanese Society for Investigative Dermatology. Published by Elsevier B.V. All rights reserved.)

Atopy is considered the epidemic of the 21st century, and while decades of research have established a direct link between Th2 cells driving pathogenic IgE-mediated allergic disease, only in the past years have T follicular helper (Tfh) cells emerged as pivotal drivers of these responses. In this review, we will examine the molecular mechanisms governing the IgE response, with a particular emphasis on the key cytokines and signaling pathways. We will discuss the exclusion of IgE-producing B cells from germinal centers and explore the recently established role of follicular T cell function and heterogeneity in driving or curtailing these immune responses. Additionally, we will assess the current state of major monoclonal antibodies and allergen immunotherapies designed to counteract Th2-driven inflammation, as well as reflect on the need to investigate how these biologics impact Tfh cell activity, differentiation, and function, as these insights could pave the way for much-needed therapeutic innovation in the treatment of allergic diseases., (Copyright © 2024 Japanese Society of Allergology. Published by Elsevier B.V. All rights reserved.)

Clinically and pathologically, the patients with hyper-IgE syndrome present similar skin manifestations to common atopic dermatitis. The original hyper-IgE syndrome is characterized by diminished inflammatory response, in combination with Staphylococcus aureus skin abscess and pneumonia followed by pneumatocele formation. These immunological manifestations are frequently associated with skeletal and connective tissue abnormalities. We previously identified that major causal variants of the hyper-IgE syndrome are dominant negative variants in the STAT3.In addition to the identification of new causative variants for the disorders similar to the original hyper-IgE syndrome, causative variants for new types of hyper-IgE syndrome centered only on atopy, high serum IgE levels, and susceptibility to infection, but not associated with diminished inflammatory response, pneumatocele formation, and connective tissue manifestations, have been identified. Recent discovery identified a novel zinc finger protein that regulates STAT3 transcription. Investigation of IL6ST variants disclosed that IL6ST/IL6R cytokine receptor plays a crucial role for the signal transduction upstream of STAT3 in the pathogenesis of the original hyper-IgE syndrome. Even if the same IL6ST variants are used for the signal transduction of IL-6 family cytokines, the signaling defect is more severe in IL-6/IL-11 and milder in LIF. The fact that the non-immune manifestations of the gain-of-function mutations of TGFBR1 and TGFBR2 are similar to the those of dominant negative mutations of STAT3 provide a clue to elucidate molecular mechanisms of non-immune manifestations of hyper-IgE syndrome. Research on this hereditary atopic syndrome is being actively conducted to elucidate the molecular mechanisms and to develop new therapeutic approaches.

Background: Disease burden is particularly high in Chronic Spontaneous Urticaria (CSU) patients with angioedema, and patients whose signs and symptoms are inadequately controlled by H1-antihistamines need new treatment options. Here we report an exploratory analysis, from the ligelizumab Phase 2b study, investigating angioedema occurrence in patients with CSU and describe the changes in angioedema following treatment with ligelizumab, omalizumab, or placebo. Methods: Data from the ligelizumab Phase 2b core (ligelizumab 72 mg, 240 mg, omalizumab 300 mg and placebo) and extension study (ligelizumab 240 mg) were used. Changes in Weekly Angioedema Activity Score (AAS7), the Dermatology Life Quality Index (DLQI), and Weekly Urticaria Activity Score (UAS7) among each time point were analyzed for each treatment arm. Results: From a total of 297 patients analyzed, 165 (55.6%) reported angioedema occurrence at baseline, with mean AAS7 ranging 30.6—42.2 across treatment arms. At Week 12 of the core study 87.5%, 84.6%, 75.0%, and 61.0% of patients were angioedema free for ligelizumab 72 mg, 240 mg, omalizumab 300 mg, and placebo arms, respectively. In CSU patients with angioedema at baseline, the largest change from baseline in AAS7 score was observed with ligelizumab 72 mg (−31.9) at week 16 in the core study. Patients with angioedema had a higher mean DLQI at baseline (14.9—16.1) vs. patients without angioedema (10.6—12.0). In patients with angioedema, low AAS7 was significantly associated with complete response on UAS7 (UAS7 = 0) and complete normalization of DLQI (DLQI 0—1). Conclusion: In the Phase 2b study, ligelizumab effectively reduced angioedema and urticaria symptoms, and improved health related quality of life in patients with moderate-to-severe CSU. Clinicaltrails.gov NCT number: NCT02477332; NCT02649218.

Allergic asthma is an inflammatory bronchial disease associated with the IgE response, allergic inflammation of the airways, recruitment of infiltrated inflammatory cells, increased mucus production, constriction of airways, and difficulty breathing. TSLP cytokine is derived mainly from airway epithelial cells and have been shown to play an essential role in the pathogenesis of asthma. This study was designed to determine the plasma protein concentrations of total IgE and TSLP cytokines in patients with chronic stable asthma. Furthermore, we examined TSLP-r in B cells and determined whether the expression of TSLP is correlated with increased total IgE. Thirty-one patients with chronic stable asthma and nineteen normal controls were enrolled in the study. Blood samples were separated using the Ficoll gradient method, and plasma and lymphocyte cells were collected. Plasma levels of total IgE and TSLP were quantified in patients with asthma and normal controls by specific ELISAs. Moreover, the surface expression of TSLP-r on B cells was analyzed using flow cytometry. Total IgE protein concentrations in the plasma of patients with chronic stable asthma (344 IU/ml, P

Silicosis is one of the most important occupational diseases worldwide, caused by inhalation of silica particles or free crystalline silicon dioxide. As a disease with high mortality, it has no effective treatment and new therapeutic targets are urgently needed. Recent studies have identified FCER1A, encoding α-subunit of the immunoglobulin E (IgE) receptor FcεRI, as a candidate gene involved in the biological pathways leading to respiratory symptoms. FcεRI is known to be important in allergic asthma, but its role in silicosis remains unclear. In this study, serum IgE concentrations and FcεRI expression were assessed in pneumoconiosis patients and silica-exposed mice. The role of FcεRI was explored in a silica-induced mouse model using wild-type and FcεRI-deficient mice. The results showed that serum IgE concentrations were significantly elevated in both pneumoconiosis patients and mice exposed to silica compared with controls. The mRNA and protein expression of FcεRI were also significantly increased in the lung tissue of patients and silica-exposed mice. FcεRI deficiency significantly attenuated the changes in lung function caused by silica exposure. Silica-induced elevations of IL-1β, IL-6, and TNF-α were significantly attenuated in the lung tissue and bronchoalveolar lavage fluid (BALF) of FcεRI-deficient mice compared with wild-type controls. Additionally, FcεRI-deficient mice showed a significantly lower score of pulmonary fibrosis than wild-type mice following exposure to silica, with significantly lower hydroxyproline content and expression of fibrotic genes Col1a1 and Fn1. Immunofluorescent staining suggested FcεRI mainly on mast cells. Mast cell degranulation took place after silica exposure, as shown by increased serum histamine levels and β-hexosaminidase activity, which were significantly reduced in FcεRI-deficient mice compared with wild-type controls. Together, these data showed that FcεRI deficiency had a significant protective effect against silica-induced pulmonary inflammation and fibrosis. Our findings provide new insights into the pathophysiological mechanisms of silica-induced pulmonary fibrosis and a potential target for the treatment of silicosis.

Type I hypersensitivity is an immediate immune reaction that involves IgE-mediated activation of mast cells. Activated mast cells release chemical mediators, such as histamine and lipid mediators, which cause allergic reactions. Recent developments in detection devices have revealed that mast cells simultaneously release a wide variety of lipid mediators. Mounting evidence has revealed that mast cell-derived mediators exert both pro- and anti-inflammatory functions and positively and negatively regulate the development of allergic inflammation. This review presents the roles of major lipid mediators released from mast cells. Author believes this review will be helpful for a better understanding of the pathogenesis of allergic diseases and provide a new strategy for the diagnosis and treatment of allergic reactions.

Background: Propolis is a resinous mixture produced by honey bees that contains cinnamic acid derivatives and flavonoids. Although propolis has been reported to inhibit mast cell functions and mast cell-dependent allergic responses, the effect of propolis on basophil biology remains unknown. This study aimed to investigate the inhibitory effect of propolis on FcεRI-mediated basophil activation. Methods: To determine the inhibitory effect of propolis on basophil activation in vitro, cytokine production and FcεRI signal transduction were analyzed by ELISA and western blotting, respectively. To investigate the inhibitory effect of propolis in vivo, IgE-CAI and a food allergy mouse model were employed. Results: Propolis treatment resulted in the suppression of IgE/antigen-induced production of IL-4, IL-6 and IL-13 in basophils. Phosphorylation of FcεRI signaling molecules Lyn, Akt and ERK was inhibited in basophils treated with propolis. While propolis did not affect the basophil population in the treated mice, propolis did inhibit IgE-CAI. Finally, ovalbumin-induced intestinal anaphylaxis, which involves basophils and basophil-derived IL-4, was attenuated in mice prophylactically treated with propolis. Conclusions: Taken together, these results demonstrate the ability of propolis to suppress IgE-dependent basophil activation and basophil-dependent allergic inflammation. Therefore, prophylactic treatment with propolis may be useful for protection against food allergic reactions in sensitive individuals.

Food allergy (FA) is a growing healthcare problem worldwide and the rising prevalence in many countries can be attributed to lifestyle, environmental, and nutritional changes. Immunoglobulin E (IgE)-mediated FA is the most common form of FA affecting approximately 3%–10% of adults and 8% of children across the globe. Food allergen–induced immediate hypersensitivity reactions mediated by IgE and high-affinity IgE receptor (FcεRI) complexes on mast cells and basophils are a major hallmark of the disease. FA can affect several aspects of health-related quality of life and impose a substantial financial burden on patients and healthcare systems. Although currently there is one United States Food and Drug Administration (FDA) and European Medicines Agency (EMA)–approved treatment for peanut allergy (Palforzia), the main treatment approaches are based on allergen avoidance and symptom management. Thus, there is an urgent need for more effective and ideally disease-modifying strategies. Given the crucial role of IgE in FA, anti-IgE monoclonal antibodies are considered promising therapeutic agents. Talizumab was the first humanized anti-IgE antibody to demonstrate substantial protection against allergic reactions from accidental peanut exposure by substantially increasing the peanut reactivity threshold on oral food challenge. However, development of talizumab was discontinued and further trials were performed using omalizumab. In double-blind, Phase 2, placebo-controlled trials in patients with multi-FAs, sustained dosing with omalizumab, or omalizumab in combination with oral immunotherapy, enabled rapid desensitization to multiple trigger foods. In this review, we describe the development of ligelizumab (a derivative of talizumab), a next generation, humanized monoclonal anti-IgE antibody, its existing clinical evidence, and its potential in the management of FA. When compared with omalizumab, ligelizumab binds with ∼88-fold higher affinity for human IgE and recognizes a different epitope that substantially overlaps with the binding site of FcεRI. These properties translate into a high potency to block IgE/FcεRI signaling in both in vitro and in vivo studies. Given its efficient suppression of IgE levels, good safety and pharmacokinetic/pharmacodynamic profile, ligelizumab clearly warrants further studies for the potential management of FA.

Background: Menthone that is a monoterpene rich in Mentha × piperita L. has been found anti-inflammatory potential for treating various diseases. However, the effect of menthone supplementation in vivo on systemic allergic inflammation in allergic asthma has not been investigated yet.Purpose: To unravel the puzzle, menthone was administered by gavage to ovalbumin (OVA)-sensitized and challenged BALB/c mice for 5 weeks to evaluate the effects on allergic asthma.Study design: There were six groups in the experiment, including dietary control (DC group, 0 mg menthone/kg b.w./day), 8 (ML group), 40 (MM group) as well as 200 mg menthone/kg b.w./day (MH group), positive control (PC group, 3 mg dexamethasone/kg b.w. before OVA challenge) and non-treatment control (NTC group, normal mice without treatment).Methods: Changes in mediators of systemic immune responses including serum antibody titers, Th1/Th2 cytokines by splenocytes and pro-/anti-inflammatory cytokines by peritoneal macrophages of the experiment mice were analyzed using ELISA.Results: As a result, menthone supplementation significantly decreased Th2-polarized OVA-specific IgG1 and IgE titers, as well as total IgE levels. Menthone supplementation dose-dependently and significantly decreased IL-4 and IL-5 (Th2) secretions by splenocytes. Menthone supplementation decreased pro-/anti-inflammatory secretion ratios (TNF-α/IL-10) by peritoneal macrophages.Conclusion: Our results suggest that menthone supplementation may effectively ameliorate systemic allergic inflammation in the allergic asthmatic mice via regulating Th2-skewed immune balance.

Lactococcus lactis subsp. cremoris YRC3780 (L. cremoris YRC3780) was isolated from kefir, and anti-allergic effects have been confirmed in humans. The mechanisms by which L. cremoris YRC3780 affects the Th1/Th2 balance in mice were investigated in vitro, focusing on the intestinal immune response. Simultaneously, a 2,4-dinitrochlorobenzene-induced atopic dermatitis mouse model was used to evaluate the symptom improvement effect of oral administration of L. cremoris YRC3780. The results showed that L. cremoris YRC3780 enhanced IFN-γ and IL-12 production and inhibited IL-4 production from CD4+ T cells in the presence of various types of immune cells. Oral administration of L. cremoris YRC3780 attenuated serum total IgE (p

IgE antibodies play a protective role against parasites and environmental toxins by its strong effector functions. However, aberrant IgE production can contribute to the development of allergic disorders, and thus is tightly regulated. Beside its very short half-life, IgE is normally produced only transiently and its affinity maturation is limited under physiological immune responses. Although such distinct characteristics of IgE among Ig classes are well-known, the underlying molecular mechanisms have not been understood until recently. Somatic or genetic defects of such mechanisms can lead to pathogenesis of allergic diseases. In this review, we summarize recent advances in our understanding of the mechanisms that control the production of IgE and formation of IgE-type humoral memory, focusing on the B cell immune responses.

Background: Allergic reactions have been observed following both direct centipede bites and the clinical use of centipede-containing medicines, such as traditional Chinese medicines utilizing Scolopendra subspinipes mutilans; however, no natural centipede allergen has yet been characterized. Methods: An allergen was purified from S. s. mutilans venom using Superdex 75 gel filtration and RESOURCE S ion chromatography, and its primary structure was determined via a combination of LC-MS-MS, MALDI-TOF/TOF and protein sequencing techniques. Its potential allergenicity was evaluated by immunoblotting, ELISAs, skin prick tests (SPTs) and mast cell activation assays. Results: A novel allergen Sco m 5 (210 amino acids long) was successfully purified from crude S. s. mutilans venom. Sco m 5 could promote the degranulation of a human mast cell line, HMC-1. Among centipede-allergic patients, Sco m 5 showed an 83.3% IgE-binding frequency and a 66.7% positive reaction frequency, as detected by immunoblotting and SPTs, respectively. Sco m 5 IgE-binding frequencies of common Chinese population was found to be 9%–16%. Sera positive for Sco m 5 IgE-binding was cross-reactive against venom from the wasp Vespa mandaeinia. Conclusions: The present study isolated and characterized a novel allergen termed as Sco m 5 from the centipede S. s. mutilans. The use of Sco m 5 to identify centipede-allergic individuals could be important, given the high potential allergenicity of Sco m 5 among the general Chinese population, along with the likely possibility of cross-reactivity against wasp venom among centipede-allergic patients.

Objective: To assess the frequency of baked egg tolerance in IgE-mediated egg allergy patients through the oral food challenge and to assess the tolerance predictability of different skin prick tests, as well as specific serum IgE measurement to egg proteins. Methods: In this cross-sectional study, 42 patients with a diagnosis of egg allergy were submitted to different skin prick tests with egg (in natura, boiled, muffin, ovalbumin, and ovomucoid), and specific IgE to egg white, ovalbumin, and ovomucoid; as well as to the oral food challenge with food containing egg, extensively baked in a wheat matrix. Results: Of the total, 66.6% of patients tolerated the ingestion of egg-containing foods in the oral food challenge. A comparative analysis with positive and negative oral food challenge found no significant differences regarding age, gender, other food allergies, or even specific skin prick tests and IgE values between the groups. Conclusions: The study demonstrated an elevated frequency of baked egg food-tolerant individuals among egg allergy patients. None of the tested markers, skin prick tests, or specific IgE, were shown to be good predictors for identifying baked egg-tolerant patients. The oral food challenge with egg baked in a matrix is central to demonstrate tolerance and the early introduction of baked foods, improving patients’ and families’ quality of life and nutrient intake. Resumo: Objetivo: Avaliar a frequência de tolerância a alimentos assados com ovo em pacientes com alergia ao ovo mediada por IgE por meio do teste de provocação oral e verificar a capacidade de predição de tolerância ao ovo por meio de teste cutâneo de leitura imediata (Skin Prick Test ou SPT) e de dosagem sérica de IgE específica para componentes do ovo. Métodos: Estudo transversal, 42 pacientes com diagnóstico de alergia ao ovo foram submetidos a SPT com ovo (in natura, cozido, bolinho, ovoalbumina e ovomucoide), IgE específica para clara de ovo, ovoalbumina e ovomucoide e ao teste de provocação oral com alimento com ovo extensamente assado em matriz de trigo. Resultados: Dos pacientes, 66,6% toleraram a ingestão do alimento com ovo durante o teste de provocação oral. Não encontramos diferenças em relação a idade, gênero, outras alergias alimentares ou mesmo entre os valores dos SPT e IgE específicas na análise comparativa entre os grupos com teste de provocação oral positivo e teste de provocação oral negativo. Conclusões: Foi demonstrada uma elevada frequência de indivíduos tolerantes a ingestão de alimentos assados com ovo entre os pacientes com alergia a ovo mediada por IgE. Nenhum dos marcadores testados, SPT ou IgE específica, demonstrou ser bom preditor para identificar os pacientes tolerantes. Consideramos que os testes de provocação oral com alimentos com ovo assado sejam fundamentais para a introdução desses assados, melhorar a qualidade de vida e a ingestão de nutrientes dos pacientes e famílias.

Background: Mast cells play a central role in innate and adaptive immunity by releasing pre-formed and de novo synthesized mediators, which include microRNAs. Although miRNAs have been confirmed to function in cell proliferation, differentiation, apoptosis, and the immune response, their functions are still limited in mast cells degranulation. Methods: Here, we survey miRNA expression profiles in activated mouse bone marrow-derived mast cells (BMMCs) with a miRNA microarray and compare the profiles to those from resting BMMCs. Partial miRNAs were selected for confirmation by qPCR, and let-7i was selected for function discover in mast cell degranulation process. TargetScan Mouse database were used for target genes prediction, gene ontology (GO) were used for gene molecular function classifications, and Cytoscape software were used to construct gene network of degranulation. Results: We found 13 up-regulated miRNAs and 7 down-regulated miRNAs in DNP activated BMMCs by miRNA microarray; and let-7b, let-7c, let-7d, let-7f, let-7i, and miR-652 were up-regulated, and miR-296-3p was down-regulated in DNP-stimulated BMMCs by qPCR. In the function research, let-7i can inhibit mast cell degranulation by suppress Exco8 expression. Overall, the data indicate that miRNAs participate in mast cell activation, especial for mast cell degranulation process.

Background: IgE bound on the surface of mast cells contributes to the pathogenesis of chronic spontaneous urticaria (CSU). Atopy is a predisposing factor for CSU, where omalizumab is a widely used monoclonal antibody to control urticaria symptoms via capturing serum free IgE. However, the role of serum free IgE is not clarified in CSU. The present study evaluated the clinical relevance of serum free IgE in patients with CSU. Methods: Eighty-eight patients with CSU and 76 healthy controls (HCs) were enrolled in this study. Serum total and Dermatophagoides pteronyssinus (Der p)-specific IgE levels were measured by ImmunoCAPs. The serum free IgE levels were measured by ELISA using a novel IgETRAP, and their associations with clinical parameters, including urticaria activity score (UAS), were evaluated. Changes in serum free and total IgE levels after omalizumab treatment were observed in 23 CSU patients in comparison between responders (≥50% reduction in UAS) and non-responders (

Background: In Japan, urticaria is a common skin disorder with chronic spontaneous urticaria (CSU) being the most frequent subtype. This study evaluated the safety of ligelizumab (anti-IgE monoclonal antibody) in Japanese CSU patients., Methods: This was a Phase 3 multicenter, open-label, single-arm 52-week study in adult Japanese patients with CSU inadequately controlled with locally approved doses of H1-antihistamines. The primary objective reported the safety of ligelizumab 120 mg subcutaneously every 4 weeks, by evaluation of treatment emergent adverse events (TEAE). Secondary objectives evaluated efficacy by absolute change from baseline (CFB) in weekly urticaria activity score (UAS7), and the proportion of patients with UAS7 = 0, and dermatology life quality index (DLQI) = 0-1 over time., Results: From a total of 66 CSU patients (80.3% females; mean ± SD age 46.4 ± 13.2 years; mean ± SD baseline UAS7 28.7 ± 6.5) enrolled, 53 patients (80.3%) reported ≥1 TEAE during the study, with no severe or serious adverse events, no anaphylaxis events and low frequency of TEAEs leading to treatment discontinuations (6.1%). Absolute mean CFB of UAS7 showed a rapid onset of response at Week 4 (-14.2) with further improvement until end of treatment at Week 52 (-22.9). The proportion of patients achieving UAS7 = 0 improved over time (14.5% at Week 4; 50.0% at Week 52). A sizable proportion of patients achieved DLQI 0-1 with the first dose of ligelizumab (38.5%), and improvements observed throughout the study until Week 52 (68.8%)., Conclusions: Treatment with ligelizumab 120 mg was well-tolerated with mild to moderate adverse events and was efficacious in Japanese patients., (Copyright © 2024 Japanese Society of Allergology. Published by Elsevier B.V. All rights reserved.)