Search

Background: Environmental exposure to peanut through non‐oral routes is a risk factor for peanut allergy. Early‐life exposure to air pollutants, including particulate matter (PM), is associated with sensitization to foods through unknown mechanisms. We investigated whether PM promotes sensitization to environmental peanut and the development of peanut allergy in a mouse model. Methods: C57BL/6J mice were co‐exposed to peanut and either urban particulate matter (UPM) or diesel exhaust particles (DEP) via the airways and assessed for peanut sensitization and development of anaphylaxis following peanut challenge. Peanut‐specific CD4+ T helper (Th) cell responses were characterized by flow cytometry and Th cytokine production. Mice lacking select innate immune signaling genes were used to study mechanisms of PM‐induced peanut allergy. Results: Airway co‐exposure to peanut and either UPM‐ or DEP‐induced systemic sensitization to peanut and anaphylaxis following peanut challenge. Exposure to UPM or DEP triggered activation and migration of lung dendritic cells to draining lymph nodes and induction of peanut‐specific CD4+ Th cells. UPM‐ and DEP‐induced distinct Th responses, but both stimulated expansion of T follicular helper (Tfh) cells essential for peanut allergy development. MyD88 signaling was critical for UPM‐ and DEP‐induced peanut allergy, whereas TLR4 signaling was dispensable. DEP‐induced peanut allergy and Tfh‐cell differentiation depended on IL‐1 but not IL‐33 signaling, whereas neither cytokine alone was necessary for UPM‐mediated sensitization. Conclusion: Environmental co‐exposure to peanut and PM induces peanut‐specific Tfh cells and peanut allergy in mice. [ABSTRACT FROM AUTHOR]

Background: Eosinophilic esophagitis (EoE) is an immune‐mediated disease, characterized by Th2‐type inflammation linked to specific foods. No currently available allergy tests reliably identify food triggers in EoE, leading to empiric dietary elimination strategies. Recently, milk‐ and wheat‐specific IgA in esophageal brushings were linked to clinical food triggers. In this study, we aimed to determine whether food‐specific IgA from esophageal biopsies is associated with known food triggers. Methods: A prior cohort of 21 patients (median age 39 years) with confirmed EoE underwent empirical elimination diets and subsequent reintroduction of foods to determine triggers. Archived baseline biopsies were used to quantify levels of peanut‐, milk‐, soy‐, egg‐, wheat‐specific and total IgA by enzyme‐linked immunosorbent assay. Results: Overall, 13 patients (62%) responded to the dietary elimination as determined by histology (<15 eos/hpf), with milk and egg being the most common triggers. Biopsies had varying amounts of total IgA, while food‐specific IgA was only detectable in 48 of 105 (46%) samples. Food‐specific IgA was normalized to total IgA for each sample and stratified by whether a food was a known trigger. For all foods tested, there were no significant differences in IgA between positive and negative triggers. Conclusions: Food‐specific IgA in esophageal biopsies was not associated with previously identified food triggers in this cohort. Future studies comparing food‐specific IgA in esophageal brushings, mucous scrapings, and biopsies from patients with known triggers will be critical to determining whether food‐specific IgA may serve as a biomarker for identification of EoE triggers. [ABSTRACT FROM AUTHOR]

Background: Indoor dust (ID) is a source of peanut proteins and immunostimulatory adjuvants (e.g. LPS) that can promote airway sensitization to peanut. We aimed to determine whether a single airway exposure to peanut plus adjuvant is sufficient to prevent oral tolerance. Methods: To determine the effect of a single priming event, C57BL/6J mice were exposed once to peanut plus adjuvant through the airway, followed by either airway or low‐dose oral exposure to peanut, and assessed for peanut allergy. Oral tolerance was investigated by feeding high‐dose peanut followed by airway sensitization. To determine whether a single priming could prevent oral tolerance, the high‐dose peanut regimen was applied after a single airway exposure to peanut plus adjuvant. Peanut‐specific IgE and IgG1 were quantified, and mice were challenged to peanut to assess allergy. Peanut‐specific CD4+ memory T cells (CD4+TCRβ+CD44hiCD154+) were quantified in mediastinal lymph nodes following airway priming. Results: Mice co‐exposed to peanut with LPS or ID through the airway were primed to develop peanut allergy after subsequent low‐dose oral or airway exposures to peanut. Oral tolerance was induced in mice fed high‐dose peanut prior to airway sensitization. In contrast, mice fed high‐dose peanut following a single airway exposure to peanut plus adjuvant led to allergy. Peanut‐specific CD4+ memory T cells were detected as early as 7 days after the single airway priming with peanut plus adjuvant, however, delaying peanut feeding even 1 day following priming led to allergy, whereas peanut feeding the same day as priming led to tolerance. Conclusions: A single airway exposure to peanut plus adjuvant is sufficient to prime the immune system to develop allergy following subsequent high‐dose oral exposure. These results highlight the importance of introducing peanut as early as possible to prevent sensitization through a non‐oral priming event. [ABSTRACT FROM AUTHOR]

To explore the effects of peanut allergy on CC027 mouse IEC function, RNA from PBS- and peanut-sensitized CC027 mouse-derived jejunal IECs before and after challenge with peanut (30, 60 and 120 min) was isolated for RNA-seq (Figure 2A). After intragastric FITC-dextran 4 kDa (FD4) administration during challenge, plasma FD4 levels in Peanut/Peanut CC027 mice were significantly higher compared with that of PBS/Peanut CC027 mice at 30, 60, 120 and 240 min after challenge (Figure 1H) but not in similarly treated C3H mice (Figure 1I). Keywords: allergy severity; angiopoietin-like 4; angptl4; barrier permeability; food allergy; intestinal epithelial cell; intestinal permeability; peanut allergy EN allergy severity angiopoietin-like 4 angptl4 barrier permeability food allergy intestinal epithelial cell intestinal permeability peanut allergy 210 215 6 02/20/23 20230201 NES 230201 Key Messages The genetically susceptible CC027/GeniUnc mouse and peanut-allergic pediatric patients demonstrate increased intestinal epithelial cell (IEC) permeability. Peanut/Peanut CC027 mouse-derived IECs, but not those from respective C3H mice, showed a significant I decrease i in TEER (Figure 1L) and I increase i in apical-to-basolateral FD4 (Figure 1M) compared with PBS/PBS CC027 mouse-derived jejunal IECs. [Extracted from the article]

Food allergy presents a significant global health concern with up to 10% of the population affected in developed nations and a steadily increasing prevalence. In many cases, particularly with peanut, tree nut and shellfish, food allergy is a lifelong and potentially life‐threatening diagnosis. While no 'cure' for IgE‐mediated food allergy exists, oral immunotherapy (OIT) is a promising treatment modality with the peanut OIT drug Palforzia (Aimmune Therapeutics) the only treatment for food allergy that is currently approved by the United States Food and Drug Administration. OIT primarily induces a state of desensitization with only a minority of subjects achieving sustained unresponsiveness, a state of limited clinical remission that appears to be immunologically distinct from natural tolerance. Early humoural changes during OIT include an initial increase in allergen‐specific IgE, which eventually decreases to below baseline levels as OIT progresses, and a gradual increase in allergen‐specific IgA and IgG4 that continues throughout the course of OIT. Basophil hyporesponsiveness and decreased skin prick test wheal size are observed within the first year of OIT, and persistence after completion of therapy has been associated with sustained unresponsiveness. In the T‐cell compartment, there is an initial expansion followed by a decline in the number and activity of T helper 2 (TH2) cells, the latter of which may be dependent on an expansion of IL‐10‐producing cells, including regulatory T‐cells. Our understanding of the immunomodulatory effects of OIT continues to evolve, with new technologies such as single‐cell transcriptional profiling and antibody epitope analysis allowing for more detailed study of T‐cell and B‐cell responses to OIT. In this review, we present evidence to illustrate what is currently known about the immunologic changes induced by OIT, explore potential mechanisms and emphasize knowledge gaps where future research is needed. [ABSTRACT FROM AUTHOR]

Introduction: Previous studies in humans support the dual‐allergen exposure hypothesis, and several studies in mouse models have demonstrated that cutaneous exposure to disrupted or intact skin can lead to sensitization to peanut. However, the field lacks definitive evidence that cutaneous exposure leads to peanut allergy in humans or other primates. Methods: Peanut extract was applied to the shaved back of the neck of four male and four female African green monkeys three times per week for 4 weeks. An oral food challenge (OFC) was performed the following week by gavage of 200 mg of peanut protein, and vital signs were monitored for 30 minutes post‐OFC. Blood was collected at baseline, day 11, day 32, and 30 minutes post‐OFC. Total IgE, and peanut‐specific immunoglobulin E (IgE) and immunoglobulin G (IgG) were quantified in serum collected throughout the 4 weeks. Histamine was measured in serum collected 30 minutes post‐OFC. Results: Peanut‐specific IgE was undetectable at any time points in any of the monkeys, and there was no consistent increase in total IgE. During the oral challenge, none of the monkeys experienced allergic symptoms and histamine levels did not change. However, seven of the eight monkeys produced increasing peanut‐specific IgG by day 32, indicating that repeated skin exposure to peanut is immunogenic. Conclusions: Skin exposure to peanut did not lead to sensitization in this study, and monkeys did not experience anaphylaxis upon peanut challenge. However, monkeys produced increased peanut‐specific IgG throughout peanut exposure, indicating that repeated skin exposure to peanut is immunogenic. [ABSTRACT FROM AUTHOR]

Background: For patients with peanut allergy, there are currently no methods to predict who will develop sustained unresponsiveness (SU) after oral immunotherapy (OIT). Objective: Assess IgE binding to peanut (PN), Ara h 2, and specific linear epitopes of Ara h 2 as predictors of the important clinical parameters: eliciting dose threshold and attainment of SU following OIT. Methods: Samples and clinical data were collected from children undergoing OIT. PN‐ and Ara h 2‐sIgE were quantified by ImmunoCAP®. IgE binding to linear peptides of Ara h 2 and Ara h 6 was measured with peptide microarrays. Results: Values of PN‐sIgE correlated with eliciting dose (P =.001) and with a higher likelihood of achieving SU (P <.0001), but these relationships were lost at higher values for PN‐sIgE (≥14 kIU for eliciting dose and ≥35 kIU/L for SU). In subjects with PN‐sIgE ≥ 14 kIU/L, binding of IgE to epitopes 5 and 6 of Ara h 2 was associated with a lower eliciting dose at baseline challenge (P <.001; Pc <.02). In subjects with PN‐sIgE ≥ 35 kIU/L, a combined model of IgE binding to epitopes 1, 5 and 6 with PN‐sIgE was highly predictive of attainment of SU (AUC of 0.86; P =.0067). Conclusion: In young patients with peanut allergy, measurement of PN‐sIgE and IgE binding to specific linear epitopes of Ara h 2 in baseline samples may allow stratification of patients regarding sensitivity to challenge and outcome of OIT. [ABSTRACT FROM AUTHOR]

Background: There is growing evidence that environmental peanut exposure through non‐oral routes, including the skin and respiratory tract, can result in peanut sensitization. Environmental adjuvants in indoor dust can promote sensitization to inhaled antigens, but whether they contribute to peanut allergy development is unclear. Objective: We investigated whether indoor dust promotes airway sensitization to peanut and peanut allergy development in mice. Methods: Female and male C57BL/6J mice were exposed via the airways to peanut, indoor dust extract, or both for 2 weeks. Mice were then challenged with peanut and assessed for anaphylaxis. Peanut‐specific immunoglobulins, peanut uptake by lung conventional dendritic cells (cDCs), lung innate cytokines, and T cell differentiation in lung‐draining lymph nodes were quantified. Innate cytokine production by primary human bronchial epithelial cells exposed to indoor dust was also determined. Results: Inhalational exposure to low levels of peanut in combination with indoor dust, but neither alone, resulted in production of peanut‐specific IgE and development of anaphylaxis upon peanut challenge. Indoor dust triggered production of innate cytokines in murine lungs and in primary human bronchial epithelial cells. Additionally, inhaled indoor dust stimulated maturation and migration of peanut‐laden lung type 1 cDCs to draining lymph nodes. Inhalational exposure to peanut and indoor dust induced peanut‐specific T helper 2 cell differentiation and accumulation of T follicular helper cells in draining lymph nodes, which were associated with increased B cell numbers and peanut‐specific immunoglobulin production. Conclusions & clinical relevance: Indoor dust promotes airway sensitization to peanut and development of peanut allergy in mice. Our findings suggest that environmental adjuvants in indoor dust may be determinants of peanut allergy development in children. [ABSTRACT FROM AUTHOR]

Background: Oral and sublingual immunotherapies for peanut allergy have demonstrated efficacy in small clinical trials; however, mechanisms and biomarkers correlating with clinical outcomes remain elusive. Previous studies have demonstrated a role for IgG in post‐OIT plasma in the suppression of IgE‐mediated mast cell reactions. Objective: The aim of this study was to characterize the role that peanut oral and sublingual immunotherapy‐induced plasma factors play in the inhibition of ex vivo basophil activation and whether inhibitory activity is associated with clinical outcomes. Methods: Plasma samples from subjects on placebo, peanut oral immunotherapy (OIT) or peanut sublingual immunotherapy (SLIT), and IgG‐depleted plasma or the IgG fraction were incubated with sensitized basophils, and the inhibition of basophil activation following stimulation with peanut extract was measured. Basophil inhibition results were compared between the two routes of immunotherapy, time on treatment and clinical outcomes. Results: Plasma from subjects after 12 months of active peanut OIT, but not placebo, inhibits basophil activation ex vivo. Depletion of IgG abrogated the blocking effect of OIT plasma, while the IgG fraction substantially blocked basophil activation. Basophils are inhibited to a similar extent by undiluted OIT and SLIT plasma; however, diluted OIT plasma from the time of desensitization challenge inhibited basophils more than diluted SLIT plasma from time of desensitization challenge. Plasma from subjects who experienced sustained unresponsiveness following OIT inhibited basophils to a greater extent than plasma from subjects who were desensitized, but this was not true for SLIT. Conclusions and Clinical Relevance: Peanut immunotherapy induces IgG‐dependent functional changes in plasma that are associated with OIT but not SLIT clinical outcomes. Understanding the mechanisms of peanut OIT and SLIT may help derive informative biomarkers. [ABSTRACT FROM AUTHOR]

Background: Mechanisms underlying oral immunotherapy (OIT) are unclear and the effects on immune cells at varying maintenance doses are unknown. Objective: We aimed to determine the immunologic changes caused by peanut OIT in preschool aged children and determine the effect on these immune responses in groups ingesting low or high‐dose peanut OIT (300 mg or 3000 mg, respectively) as maintenance therapy. Methods: Blood was drawn at several time‐points throughout the OIT protocol and PBMCs isolated and cultured with peanut antigens. Secreted cytokines were quantified via multiplex assay, whereas Treg and peanut‐responsive CD4 T cells were studied with flow cytometry. Basophil activation assays were also conducted. Results: Th2‐, Th1‐, Th9‐ and Tr1‐type cytokines decreased over the course of OIT in groups on high‐ and low‐dose OIT. There were no significant differences detected in cytokine changes between the high‐ and low‐dose groups. The initial increase in both the number of peanut‐responsive CD4 T cells and the number of Tregs was transient and no significant differences were found between groups. Basophil activation following peanut stimulation was decreased over the course of OIT and associated with increased peanut‐IgG4/IgE ratios. No differences were found between high‐ and low‐dose groups in basophil activation at the time of desensitization or sustained unresponsiveness oral food challenges. Conclusions and Clinical Relevance: Peanut OIT leads to decreases in pro‐allergic cytokines, including IL‐5, IL‐13, and IL‐9 and decreased basophil activation. No differences in T cell or basophil responses were found between subjects on low or high‐dose maintenance OIT, which has implications for clinical dosing strategies. [ABSTRACT FROM AUTHOR]

Abstract: The reactivity between rare‐earth (RE‐) oxide stabilized ZrO2 or HfO2 thermal barrier coatings (TBCs) and a calcium‐magnesium‐aluminum‐silicate (CMAS) melt was studied at 1310°C. These reactions are representative of the ingestion of siliceous materials by the intake air of gas turbines (e.g., in aircraft engines) at high temperatures (>1200°C). These materials can melt and react with coated components in the hot section, resulting in premature failure. The goal of this work was to probe the effect of various RE (RE = Y, Yb, Dy, Gd, Nd, and Sm) oxides in the melt phase equilibrium and stability of the top‐coating system. Thermodynamic calculations of the phase assemblage of the (1−x) ZrO2‐xY2O3 coating materials and CMAS melt are compared with the experimental findings. CMAS was found to penetrate the samples at the grain boundaries and dissolve the coating materials to form silicate phases containing the RE elements. Furthermore, apatite and garnet crystalline phases formed in the samples with total RE‐oxide content higher than 16 mol% in the reaction zone for the ZrO2 system. In general, samples with nominal compositions ZrO2‐9Dy2O3, HfO2‐7Dy2O3, ZrO2‐8Y2O3, HfO2‐6Er2O3, ZrO2‐9.5Y2O3‐2.25Gd2O3‐2.25Yb2O3, and ZrO2‐30Y2O3 exhibited lower reactivity, or more resistance, to CMAS than the other coating compositions. [ABSTRACT FROM AUTHOR]

Tantalum pentoxide (Ta2O5) and its solid solution phases are candidate coatings for components to be used in combustion environments. Thus, it is important to understand the response of Ta2O5 to high-temperature water vapor, a product of combustion. Thermogravimetric methods are used to examine the oxide in reactant streams of controlled water vapor contents at 1250°C-1450°C. The observed weight loss indicates a reaction of the general form ½ Ta2O5(s) + x H2O(g)=TaOy( OH) x(g). Methodical variation in the water vapor pressure suggests the products are a mix of TaO( OH)3(g) and Ta( OH)5(g). Evidence of TaO( OH)3(g) was observed with a sampling mass spectrometer. The measured hydroxide and oxyhyroxide vapor fluxes from Ta2O5 are compared with calculated vapor fluxes from SiO2 and Al2O3. Ta2O5 exhibits fluxes similar to those from SiO2 due to gaseous metal hydroxide formation. [ABSTRACT FROM AUTHOR]