Allergen-specific IgE Production Research Articles

Indirubin induces tolerogenic dendritic cells via aryl hydrocarbon receptor activation and ameliorates allergic asthma in a murine model by expanding Foxp3-expressing regulatory T cells

BackgroundAllergic asthma is a chronic bronchial inflammatory disease closely associated with abnormal immune responses of dendritic cells (DCs) and allergen-specific type 2 T helper (Th2) cells. Indirubin (IR), a natural aryl hydrocarbon receptor (AhR) ligand, exerts anti-inflammatory and immunomodulatory properties. PurposeIn this study, we aimed to clarify whether IR exhibits immunomodulatory action on DCs via AhR activation and investigated the antiallergic effects of IR in a mouse model of allergic asthma. MethodsLipopolysaccharide (LPS)-activated bone marrow-derived DCs were treated with IR. Their mRNA expressions, cytokine production, and phenotype patterns were determined by a quantitative real-time PCR, ELISA, flow cytometry, and RNA sequencing. The mixed lymphocyte reaction was utilized to evaluate the regulatory function of IR-treated DCs on T-cell differentiation. Moreover, mice with ovalbumin (OVA)-induced allergic asthma were treated with IR. Thereafter, the airway hyperresponsiveness (AHR), allergen-specific IgE production, cytokine levels, airway inflammation, and T-cell responses were evaluated. ResultsTreatment of LPS-stimulated DCs with 20 μM IR significantly reduced IL-12 and TNF-α production while increasing IL-10 secretion. Meanwhile, these DCs expressed decreased levels of CD80 but increased levels of Jagged 1 surface molecules. However, the effects of IR on DCs were reversed by pretreatment with the AhR antagonist, CH223191. Additionally, the coculture of these tolerogenic-like DCs with allogeneic CD4+T cells promoted the generation of Foxp3+ regulatory T (Treg) cells. A transcriptomic analysis identified several downregulated genes that are involved in regulating cell migration, cytokine secretion, and inflammatory responses in DCs after IR treatment. In an asthmatic murine model, oral administration of 25 mg kg-1 body weight of IR efficiently alleviated the development of AHR, OVA-specific IgE production, and levels of Th2-type cytokines (IL-4, IL-5, and IL-13) and the CCL11 chemokine. IR treatment also attenuated inflammatory cell recruitment and mucus production in the lungs. Notably, an enhanced frequency of Foxp3+ Treg cells and reduced effector T-cell proliferation associated with increased levels of IL-10 and TGF-β were observed in IR-treated mice. ConclusionIR can induce tolerogenic-like BMDCs which promote the differentiation of Treg cells. Importantly, the expansion of Foxp3+ Treg cells contributed to the therapeutic efficacy of IR against allergic asthma.

Inhibition of TLR4 and NLRP3 leads to the exacerbation of IgE specific antibodies in mouse allergic models based on subcutaneous or intranasal immunization respectively

A significant increase in the prevalence of diseases linked with IgE production can be seen in recent years, but the question about the role of TLR receptors in this process remains controversial. According to the hygiene hypothesis, the decrease of the contact of the individual with pathogens that contain PRR receptor ligands in the recent years leads to the development of allergic diseases. The aim of this work was to investigate whether TLR4 and NLRP3 receptor activation contributes to allergen-specific antibody formation. BALB/c mice were immunized according to two different protocols. In the first one, OVA antigen was administered in 0.1 µg dose 2-3 times a week for 6 weeks by subcutaneous route. In the second one, OVA was administered in 0.3 µg dose intranasally in combination with 4 ng of benzo(a)pyrene (BaP) 2 times a week for 8 weeks. In both cases, TLR4 and NLRP3 receptor inhibitors, namely TLR4-IN-C34 in 1 mg/kg dose and CY- 09 in 20 mg/kg dose respectively were also administered to the some of the mice. Specific antibody production was determined by ELISA. Immunization of mice with TLR4-IN-C34 significantly (p 0.01) amplify IgE production (about 2.5 times in comparison with control group), but has no effect on specific IgG1 production in subcutaneous model. Specific IgE titers in the control group immunized without small molecule inhibitor and in the TLR4-IN-C34 group were (3±0.6) × 103 and (8±2) × 103, respectively. In this model, CY-09 administration has no effect on humoral immune response. In the secondary (intranasal) model, BaP significantly increase specific IgE and IgG1 production. CY-09 but not TLR4-IN-C34 administered in combination with BaP significant (p 0.05) and approximately 2 times enhances specific IgE but not IgG1 production. Specific IgE titers in the control group without inhibitor and in the CY-09 group were (2.0±0.4) × 102 and (5.1±0.3) × 102, respectively. So, PRR-activation, in our case activation of TLR4 in the model based on subcutaneous immunization or NLRP3 in the model based on intranasal antigen administration with BaP suppressed the production of allergen-specific IgE, but not IgG1. These data are in consistent with the hygiene theory of allergy development.

Recent advances in the practical management of allergic rhinitis.

Allergic rhinitis (AR) is a widespread disease, and its prevalence is still growing. AR may be associated with other diseases, including conjunctivitis, rhinosinusitis, asthma, food allergy, and atopic dermatitis. Diagnosis is based on history, physical examination, documentation of sensitization, such as the production of allergen-specific IgE, also using molecular diagnostics in selected patients. Treatments is based on education, engagement, allergen avoidance, non-pharmacological and pharmacological remedies, and allergen-specific immunotherapy (Ait). Symptomatic treatments mainly concern intranasal/oral antihistamines and/or nasal corticosteroids. This article also aims to discuss new management strategies for AR patients. The self-management of allergic rhinitis could include new strategies. In this regard, particular interest should be considered to intranasal corticosteroids and antihistamines without medical prescription, probiotics and other natural substances, and new formulations (tablets) of Ait.

Chemical chaperone TUDCA selectively inhibits production of allergen-specific IgE in a low-dose model of allergy.

The cellular response to endoplasmic reticulum (ER) stress accompanies plasma cell maturation and is one of triggers and cofactors of the local inflammatory response. Chemical chaperones, low-molecular substances that eliminate pathological ER stress, are proposed as means of treating pathologies associated with ER stress. The aim of this study was to evaluate the effect and mechanisms of influence of chemical chaperones on the humoral response in a low-dose model of allergy. The allergic immune response was induced in BALB/c mice by repeated administration of ovalbumin at a dose of 100 ng for 6 weeks. Some animals were injected with both the antigen and the chemical chaperones, TUDCA (tauroursodeoxycholic acid) or 4-PBA (4-phenylbutyrate). Administration of TUDCA, but not 4-PBA, suppressed production of allergen-specific IgE (a 2.5-fold decrease in titer). None of the chemical chaperones affected the production of specific IgG1. The effect of TUDCA was associated with suppression of the switch to IgE synthesis in regional lymph nodes. This phenomenon was associated with suppressed expression of genes encoding cytokines involved in type 2 immune response, especially Il4 and Il9, which in turn could be caused by suppression of IL-33 release. In addition, TUDCA significantly suppressed expression of the cytokine APRIL, and to a lesser extent, BAFF. Thus, TUDCA inhibition of the allergy-specific IgE production is due to suppression of the release of IL-33 and a decrease in the production of type 2 immune response cytokines, as well as suppression of the expression of the cytokines APRIL and BAFF.

Influence of Cordyceps militaris-fermented grain substrate extracts on alleviating food allergy in mice

BackgroundCordyceps militaris is recognized as a tonic in traditional Chinese medicine, and there have been documented findings on the anti-allergic properties of its extract derived from the fruiting body. Due to the limited availability of wild C. militaris, a specialized grain substrate has been devised for the solid-state fermentation of its fruiting bodies. However, the fermented grain substrate is considered waste and usually used as feeds for animals. To achieve the sustainable development goals, C. militaris-fermented grain substrate (CFGS) was collected to prepare CFGS extracts. Further, the anti-allergic properties of these extracts were assessed with the aim of exploring novel applications. MethodsThe water extract and ethanol extract of CFGS were prepared, and their potential in alleviating allergic enteritis was assessed in mice with food allergy. Assessment of immunomodulatory effects included the measurement of serum antibodies and splenic cytokines. Additionally, influence of extracts on gut microbiota composition was examined through sequencing analysis of 16S rRNA gene from freshly collected feces of the mice. ResultsDaily administration of the water and ethanol extracts, at doses of 50 or 250 mg/kg body weight, demonstrated a notable alleviation of allergic diarrhea and enteritis. This was accompanied by a decrease in mast cell infiltration in the duodenum and a reduction in allergen-specific IgE production in the serum. Both extracts led to a significant decrease in IL-4 secretion. Conversely, there was an increase in IFN-γ, IL-10, and TGF-β secretion from splenocytes. Remarkably, allergic mice exhibited a distinct fecal microbiota profile compared to that of normal mice. Intriguingly, the administration of these extracts had varying effects on the fecal microbiota. ConclusionTaken together, these findings collectively indicate the potential of CFGS extracts as promising candidates for functional foods. These extracts show promise in managing allergic enteritis and modulating gut microbiota.

Influence of Porphyra-derived polysaccharides and oligosaccharides on attenuating food allergy and modulating enteric microflora in mice

ABSTRACT Recently, there have been reports on the immunomodulatory properties of polysaccharides (PP), oligosaccharides (PO), and mixtures of PO/PP derived from Porphyra. To explore their potential in alleviating allergic responses and enteric dysbiosis, this study delved deeper into their effects using a murine model of food allergy. Daily administration of Porphyra samples mitigated allergic diarrhea, enteritis, and allergen-specific IgE production. Moreover, Porphyra samples exerted a significant reduction in the secretion of IL-2, IL-4, IFN-γ, and IL-17A, along with an elevation in the IL-10/IL-4 ratio in splenocytes upon allergen stimulation. Similarly, expression of IL-4 and IFN-γ in the duodenum was suppressed. Notably, allergic mice displayed a distinct fecal microflora profile compared to that of normal mice. Interestingly, PP and PO treatments exhibited different effects on improving enteric dysbiosis. These findings collectively suggest the potential of PP and PO as functional food candidates for the management of allergic enteritis and dysbiosis.

B cell intrinsic Toll-like receptor 9 signaling regulates class switching to IgE

Abstract Chronic allergic diseases such as allergic asthma are driven by excessive production of allergen specific IgE. B cells produce IgE by class switch recombination (CSR) in response to T cell help and Th2 cytokines. However, development of allergic diseases can also be influenced by factors such as early-life exposure to microbial products. In vivo, stimulation of Toll-like receptor 9 (TLR9) with microbial DNA reduces IgE levels, largely thought to be a response to Th1 cytokines. However, the directeffects of TLR9 signaling on B cell class switching to IgE remain unclear. To delineate the B cell intrinsic effects of TLR9 stimulation, we treated mouse splenic B cells in vitrowith IL-4 and anti-CD40 antibody with or without a synthetic TLR9 agonist, CpG oligodeoxynucleotides (CpG). Compared to stimulation with IL-4 and anti-CD40 alone, the addition of CpG decreased IgE production. Using B cells from reporter mice that track germline transcription, a prerequisite for CSR, we found that CpG inhibited Iɛ but increased Iγ1 germline transcription. By Western blot analyses, we probed the expression of transcription factors known to negatively regulate Iɛ and positively regulate Iγ1 transcription. These transcription factors were synergistically upregulated in the presence of CpG with IL-4 and anti-CD40. Together, these data illustrate a molecular mechanism by which microbial products directly perturb the production of IgE and influence the development of allergic disease. R01 HL165120

Histamine 3 receptor antagonism mitigates neuroinflammation and depression-like behavior in a mouse model of food allergy

Abstract Histamine (HA) is a major allergic response mediator as well as a neuromodulatory neurotransmitter and a blood-brain barrier (BBB) regulator. Consequently, dysregulation of the central histaminergic system could offset brain homeostasis and function. Indeed, mood and behavioral disorders are often comorbid with conditions that elevate systemic HA, such as mastocytosis and allergy. We have previously shown elevated levels of brain HA and its receptor subtype H3 (H3R) in a mouse model of cow’s milk allergy (CMA). Additionally, neuroinflammation and cortical demyelination were observed in association with depression-like behavior in CMA mice. However, whether the elevated HA and H3R were responsible for the development of these cellular and behavioral pathologies is unknown. We hypothesized that the elevated brain HA leads to central histaminergic dysfunction through H3R, ultimately resulting in cortical demyelination and aberrant behaviors. To investigate the role of H3R, CMA mice were treated daily with thioperamide, a selective BBB-permeable H3R antagonist, to block the action of HA through this receptor. Despite the production of allergen-specific IgE, thioperamide prevented depression-like behavior. Thioperamide also ameliorated CMA-associated cortical demyelination and axonal loss compared to saline-treated mice. Our findings strongly suggested that H3R signaling contributed to cortical demyelination and the development of depression-like behaviors in our CMA mice. Targeting HA production or signaling may provide a therapeutic strategy to reduce the risk of neurodegeneration and associated brain dysfunction in susceptible individuals. Supported by grants from NIH (1R01AI168563-01, P20GM113123-06, and P20GM103442).

Local Allergen-Specific IgE Production in Turbinate Tissue of Pediatric Patients.

The objective of this study is to compare serum allergen-specific IgE to IgE levels in nasal tissue taken from the inferior turbinates of pediatric patients undergoing turbinate reduction. Twenty-six pediatric patients were recruited at the time of turbinate reduction surgery. At the time of recruitment, parents of patients completed the validated 22 item Sinonasal Outcome Test (SNOT-22) to describe symptoms prior to surgery. A sample of turbinate tissue was taken during turbinate reduction and blood was collected. Tissue and serum IgE were measured and differences in the group characteristics were evaluated using Chi-square tests for binary variables and Wilcoxon-Mann-Whitney tests for continuous variables. Student's t test was used to assess differences in means of total SNOT-22 scoring between the groups, and Wilcoxon-Mann-Whitney tests were used again for the rest of the SNOT-22 analysis. Levels of IgE in the serum were compared to levels in the turbinate tissue from all patients for each individual allergen. Every allergen except Alternaria displayed significant correlation between the serum and turbinate IgE levels. Additionally, each allergen except Alternaria and oak tree resulted in a strong correlation (r > .7) based on the correlation coefficients. Levels of Alternaria were found to be poorly correlative between serum and turbinate tissue, and significance was not achieved (r = -.346, P = .11). Certain allergen-specific IgE antibodies in the nasal mucosa seem to be highly associated with those in the serum, based upon the significant correlations we found between the two.

Oral Tolerance Induction-Opportunities and Mechanisms.

Oral tolerance is the active absence of response to food allergens, which involves complex mechanisms in the gut-associated lymphoid tissue. Food allergy results from the disruption of such tolerance or the absence of its establishment in the first place. It follows allergic sensitization with the production of allergen-specific IgE and results from the degranulation of basophils and mast cells on subsequent exposure to the allergen. Oral tolerance induction has been explored in the contexts of prevention and treatment of food allergy. Early introduction of allergenic foods (i.e., egg and peanut) in the diet of infants, before allergic sensitization occurs (i.e., via inflamed skin affected with eczema) has shown to be beneficial. Guidelines have changed to recommend the introduction of these allergenic foods by 6 months of age. For food allergic individuals, oral tolerance induction has been attempted using allergen-specific immunotherapy, which involves the administration of an allergen, modified or not, through various possible routes, including oral, sublingual, epicutaneous, and subcutaneous, with or without concomitant administration of antibody-based biologics. Further research into the immune mechanisms of food allergy and oral tolerance can lead to the identification of novel targets to suppress the food allergic response and reverse the current food allergy epidemic.

Heterogeneity, subsets, and plasticity of T follicular helper cells in allergy

Antibody responses are critical for protection against pathogens. However, diseases such as allergic rhinitis or food allergy result from aberrant production of IgE antibodies against otherwise innocuous environmental antigens. The production of allergen-specific IgE requires interaction between B cells and CD4⁺ T cells, and a granular understanding of these interactions is required to develop novel therapies for allergic disease. CD4⁺ T cells are exceptionally heterogeneous in their transcriptional, epigenetic, and proteomic profiles, which poses significant challenges when attempting to define subsets relevant to the study of allergy among a continuum of cells. Defining subsets such as the T follicular helper (T_FH) cell cluster provides a shorthand to understand the functions of CD4⁺ T cells in antibody production and supports mechanistic experimentation for hypothesis-driven discovery. With a focus on allergic disease, this Rostrum article broadly discusses heterogeneity among CD4⁺ T cells and provides a rationale for subdividing T_FH cells into both functional and cytokine-skewed subsets. Further, it highlights the plasticity demonstrated by T_FH cells during the primary response and after recall, and it explores the possibility of harnessing this plasticity to reprogram immunity for therapeutic benefit in allergic disease.

Home Dust Mites Promote MUC5AC Hyper-Expression by Modulating the sNASP/TRAF6 Axis in the Airway Epithelium.

House dust mites (HDMs) are a common source of respiratory allergens responsible for allergic asthma and innate immune responses in human diseases. Since HDMs are critical factors in the triggering of allergen-induced airway mucosa from allergic asthma, we aimed to investigate the mechanisms of Toll-like receptors (TLR) in the signaling of the HDM extract that is involved in mucus hypersecretion and airway inflammation through the engagement of innate immunity. Previously, we reported that the somatic nuclear autoantigenic sperm protein (sNASP)/tumor necrosis factor receptor-associated factor 6 (TRAF6) axis controls the initiation of TLRs to maintain the homeostasis of the innate immune response. The present study showed that the HDM extract stimulated the biogenesis of Mucin 5AC (MUC5AC) in bronchial epithelial cells via the TLR2/4 signaling pathway involving MyD88 and TRAF6. Specifically, sNASP binds to TRAF6 in unstimulated bronchial epithelial cells to prevent the activation of TRAF6-depenedent kinases. Upon on HDMs’ stimulation, sNASP is phosphorylated, leading to the activation of TRAF6 downstream of the p38 MAPK and NF-κB signaling pathways. Further, NASP-knockdown enhanced TRAF6 signaling and MUC5AC biogenesis. In the HDM-induced mouse asthma model, we found that the HDM extract promoted airway hyperresponsiveness (AHR), MUC5AC, and allergen-specific IgE production as well as IL-5 and IL-13 for recruiting inflammatory cells. Treatment with the PEP-NASP peptide, a selective TRAF6-blocking peptide, ameliorated HDM-induced asthma in mice. In conclusion, this study indicated that the sNASP/TRAF6 axis plays a regulatory role in asthma by modulating mucus overproduction, and the PEP-NASP peptide might be a potential target for asthma treatment.

PD-1 blockade in T follicular helper cells protects mice from peanut allergy by promoting production of low-affinity antibodies

Abstract Food allergy, such as peanut allergy can cause life-threatening anaphylaxis. While T follicular helper (Tfh) cells play a major role in production of allergen-specific IgE and IgG antibodies, the immunologic mechanisms that regulate the production of antibodies that mediate anaphylaxis are not well understood. While PD-1 is highly expressed on Tfh cells, our knowledge is limited regarding the role of the molecule in Tfh cells. Thus, the objective of this study was to investigate the roles of PD-1 in allergic immune responses using a mouse model of peanut allergy. Naïve wild-type mice were exposed to peanut flour intranasally (i.n.) and then challenged by intraperitoneal (i.p.) injection of peanut extract. The mice exposed i.n. to peanut flour produced peanut-specific IgE and IgG antibodies and developed anaphylaxis when challenged i.p. with peanut extract. PD-1 blockade with anti-PD-1 treatment Tfh and germinal center B cell numbers in mice exposed to peanut flour. Nonetheless, anti-PD-1 or anti-PD-L1 fully protected mice from anaphylaxis. Anti-PD-1 or genetic deficiency of PD-1 in CD4+ T cells reduced and increased levels of peanut-specific IgE and IgG, respectively. Anti-PD-1 promoted production of low-affinity IgE and IgG antibodies with no effect on high-affinity antibodies. By passive cutaneous anaphylaxis, peanut-specific antibodies generated in anti-PD1 treated mice failed to induce anaphylaxis, and plasma from these mice prevented anaphylaxis. Therefore, blockade of the PD-1 pathway is protective against allergic immune responses. The interaction between Tfh cells and B cells may play a pivotal role in controlling antibody quality and clinical manifestation of allergic diseases.

Peripheral IgE+ plasmablasts as a biomarker of clinical allergy onset and severity

Abstract IgE-mediated allergies depend on the continuous production of allergen-specific IgE to maintain allergic sensitization. While IgE+ plasma cells are the primary source of this IgE, IgE+ plasmablasts can provide a snapshot in peripheral blood of the current response to allergen. We developed a novel approach to characterize IgE+ plasmablasts in peripheral blood and determined the relationship between allergen exposure, IgE+ plasmablasts and clinical disease. We used a unique large animal model of naturally occurring allergy, equine Culicoides hypersensitivity, which allowed all individuals to have similar timing and frequency of allergen exposure and allowed longitudinal collection of samples from the same allergic and healthy individuals over time. We found that peripheral IgE+ plasmablasts spontaneously secrete IgE, express high levels of the IgE receptor CD23 on their surface, and positively correlate with clinical disease severity. In conclusion, IgE+ plasmablasts are critical in the mechanism of allergy through IgE secretion and serve as a quantitative biomarker of allergic disease development and severity. This work was supported by the Harry M. Zweig Memorial Fund for Equine Research at Cornell University; the USDA/NIFA [#2005-01812, #2015-67015-23072, and #2019-67015-29833]; and National Institutes of Health [#1S10RR025502 through Cornell University’s Biotechnology Resource Center].

Murine model of steroid-resistant neutrophilic bronchial asthma as an attempt to simulate human pathology

Bronchial asthma (BA) is a heterogeneous chronic inflammatory disease of the airways. The majority of patients with mild to moderate BA develop Th2-biased eosinophilic pulmonary inflammation and respond well to corticosteroid treatment. However up to 10% of BA patients develop severe pathology, which is associated with neutrophilic inflammation and resistant to conventional corticosteroid therapy. Contrary to eosinophil-predominant airway inflammation neutrophilic BA is developed through Th1- and Th17-immune responses. However, the etiology of corticoid insensitive neutrophilic BA is still remains unclear. Therefore, in the current study we developed a mouse model of BA with predominant neutrophilic rather than eosinophilic pulmonary inflammation. BALB/c mice were immunized with the mixture of the ovalbumin allergen and Freund's adjuvant, followed by aerosol challenge with the same allergen mixed with E. coli lipopolysaccharide. As a result, mice developed the main BA manifestations: production of allergen specific IgE, development of airway hyperreactivity, airway remodeling and pulmonary neutrophilic inflammation. Moreover, this pathology developed through Th1- and Th17-dependent mechanisms and mice with induced neutrophilic BA phenotype responded poorly to dexamethasone treatment, that coincide to clinical observations. The established mouse model could be useful both for studying the pathogenesis and for testing novel approaches to control neutrophilic BA.

The bile acid-activated retinoic acid response in dendritic cells is involved in food allergen sensitization.

Alteration of commensal microbiota is highly correlated with the prevalence of allergic reactions to food in the gastrointestinal tract. The mechanisms by which microbiota modulate food allergen sensitization in the mucosal site are not fully understood. We generate DCs specific knockout of retinoic acid receptor α (Rara) gene mice (DC KO Rara) to evaluate food sensitization. The bile acid-activated retinoic acid response was evaluated by flow cytometry, real-time RT-PCR and Illumina transcriptome sequencing. The global effect of Abx treatment on BA profiles in the mucosal lymph tissue mLN in mice was examined by UPLC-MS analysis. In this study, we demonstrate that depletion of commensal gut bacteria leads to enhanced retinoic acid (RA) signaling in mucosal dendritic cells (DCs). RA signaling in DCs is required for the production of food allergen-specific IgE and IgG1. Antibiotics induced an enlarged bile acid (BA) pool, and dysregulated BA profiles contributed to enhanced RA signaling in mucosal DCs. BA-activated RA signaling promoted DC upregulation of interferon I signature, RA signature, OX40L, and PDL2, which may lead to T helper 2 differentiation of CD4+ T cells. BA-activated RA signaling involved the farnesoid X receptor and RA receptor α (RARa) interaction. Depletion of bile acid reduces food allergen specific IgE and IgG1 levels in mice. Our research unveils a mechanism of food sensitization modulated by BA-RA signaling in DCs, which suggests a potential new approach for the intervention of food allergic reactions.

Biology and dynamics of B cells in the context of IgE-mediated food allergy.

An increasing number of people suffer from IgE-mediated food allergies. The immunological mechanisms that cause IgE-mediated food allergy have been extensively studied. B cells play a key role in the development of IgE-mediated food allergies through the production of allergen-specific antibodies. While this particular function of B cells has been known for many years, we still do not fully understand the mechanisms that regulate the induction and maintenance of allergen-specific IgE production. It is still not fully understood where in the body IgE class switch recombination of food allergen-specific B cells occurs, and what processes are involved in the immunological memory of allergen-specific IgE responses. B cells can also contribute to the regulation of allergen-specific immune responses through other mechanisms such as antigen presentation and cytokine production. Recent technological advances have enabled highly detailed analysis of small subsets of B cells down to the single-cell level. In this review, we provide an overview of the current knowledge on the biology of B cells in relation to IgE-mediated food allergies.

Latent 1,3-β-D-glucan acts as an adjuvant for allergen-specific IgE production induced by Japanese cedar pollen exposure

BackgroundThe pollen grains of several plant species contain 1,3-β-D-glucan (BG). BG activates dendritic cells (DCs) and subsequently regulates the innate immune responses. Within Japan, the most common disease associated with type-I hypersensitivity is Japanese cedar pollinosis. However, the role of BG in Japanese cedar pollen (JCP) remains unclear. This study examined the localization and immunological effects of BG in JCP. MethodsThe localization of BG in JCP grain was determined by immunohistochemical staining using a soluble dectin-1 protein probe and a BG recognition protein (BGRP). The content of BG extracted from JCP was measured by a BGRP-based ELISA-like assay. The cytokine production by bone marrow-derived DCs (BMDCs) obtained from wild-type and BG receptor (dectin-1) knock-out mice was examined in vitro. The mice were intranasally administered JCP grains and the specific serum Ig levels were then quantified. ResultsBG was detected in the exine and cell wall of the generative cell and tube cell of the JCP grain. Moreover, BG in the exine stimulated production of TNF-α and IL-6 in the BMDCs via a dectin-1-dependent mechanism. Meanwhile, JCP-specific IgE and IgG were detected in the serum of wild-type mice that had been intranasally administered with JCP grains. These mice also exhibited significantly enhanced sneezing behavior. However, dectin-1 knock-out mice exhibited significantly lower JCP-specific IgE and IgG levels compared to wild-type mice. ConclusionsLatent BG in JCP can act as an adjuvant to induce JCP-specific antibody production via dectin-1.

Spontaneous antibody production caused by regulatory T cell deficiency occurs through a germinal center-independent pathway

Foxp3+ regulatory T cells (Tregs) are essential for the prevention of autoantibody and allergen-specific IgE production. Treg deficiency causes an elevation of the serum levels of these pathogenic antibodies, accompanied by spontaneous germinal center (GC) formation. However, it remains to be determined whether excessive and pathogenic antibody production induced by Treg deficiency requires a GC response. Here, we demonstrate that spontaneous antibody production observed in Foxp3 conditional-knockout mice did not need GC formation. Foxp3 and Bcl6 conditional-double knockout mice exhibited spontaneous elevations of IgG1, IgG2c, and IgE levels even though they showed impaired production of IgG1 and IgE specific for the immunized antigen. Furthermore, the IgG1 and IgE antibodies specific for auto- and food-antigens were produced independently of GCs. These data suggested that a GC response was unnecessary for pathogenic antibody production caused by Treg deficiency.

Obesity alters the immune landscape of the small intestine and exacerbates food allergy

Abstract In the past few decades, higher rates of obesity have coincided with a rising number of individuals affected by allergic disease. Our study objective was to determine if obesity alters the immune cell landscape of the small intestine towards an inflammatory environment that aggravates the development of food allergy. Obesity was induced by feeding male BALB/c mice a western diet for 8 weeks. To induce food allergy, mice were epicutaneously sensitized and orally-challenged with OVA. Compared with lean controls, sensitized obese mice showed a lower body temperature after challenge and increased OVA-specific IgE in serum, suggesting an exacerbated allergic response. Mass cytometry analysis of the intestinal lamina propria revealed that OVA-sensitized obese mice had decreased T regulatory cells, which are critical for the oral tolerance to food allergens. In the mesenteric lymph node, obese mice showed increased frequencies of T follicular helper cells (Tfh) compared with lean controls. Tfh cells are required for the production of allergen-specific IgE, and implicated in allergic disease pathogenesis. To further define the transcriptional mechanisms underpinning the increased inflammatory and allergic responses during obesity, we performed single-cell RNA sequencing of more than 28,000 barcoded CD45+ enriched lamina propria cells from lean and obese mice, with and without OVA sensitization. We provide a transcriptional map of inflammatory cells and define a module of gene expression that distinguishes immune cell-driven allergic responses in the obese intestine. Overall, our findings highlight obesity-induced inflammatory changes in the intestine that may mediate the increased food allergic sensitization during obesity.