TCF1-LEF1 co-expression identifies a multipotent progenitor cell (TH2-MPP) across human allergic diseases.

Repetitive exposure to antigen in chronic infection and cancer drives T cell exhaustion, limiting adaptive immunity. In contrast, aberrant, sustained T cell responses can persist over decades in human allergic disease. To understand these divergent outcomes, we employed bioinformatic, immunophenotyping and functional approaches with human diseased tissues, identifying an abundant population of type 2 helper T (TH2) cells with co-expression of TCF7 and LEF1, and features of chronic activation. These cells, which we termed TH2-multipotent progenitors (TH2-MPP) could self-renew and differentiate into cytokine-producing effector cells, regulatory T (Treg) cells and follicular helper T (TFH) cells. Single-cell T-cell-receptor lineage tracing confirmed lineage relationships between TH2-MPP, TH2 effectors, Treg cells and TFH cells. TH2-MPP persisted despite in vivo IL-4 receptor blockade, while thymic stromal lymphopoietin (TSLP) drove selective expansion of progenitor cells and rendered them insensitive to glucocorticoid-induced apoptosis in vitro. Together, our data identify TH2-MPP as an aberrant T cell population with the potential to sustain type 2 inflammation and support the paradigm that chronic T cell responses can be coordinated over time by progenitor cells.

Interferon-γ signaling in eosinophilic esophagitis has implications for epithelial barrier function and programmed cell death.

Objective: Eosinophilic esophagitis (EoE) is a chronic esophageal inflammatory disorder characterized by eosinophil-rich mucosal inflammation and tissue remodeling. Transcriptional profiling of esophageal biopsies has previously revealed upregulation of type I and II interferon (IFN) response genes. We aim to unravel interactions between immune and epithelial cells and examine functional significance in esophageal epithelial cells. Design: We investigated epithelial gene expression from EoE patients using single-cell RNA sequencing and a confirmatory bulk RNA-sequencing experiment of isolated epithelial cells. The functional impact of interferon signaling on epithelial cells was investigated using in vitro organoid models. Results: We observe upregulation of interferon response signature genes (ISGs) in the esophageal epithelium during active EoE compared to other cell types, single-cell data, and pathway analyses, identified upregulation in ISGs in epithelial cells isolated from EoE patients. Using an esophageal organoid and air-liquid interface models, we demonstrate that IFN-γ stimulation triggered disruption of esophageal epithelial differentiation, barrier integrity, and induced apoptosis via caspase upregulation. We show that an increase in cleaved caspase-3 is seen in EoE tissue and identify interferon gamma (IFNG) expression predominantly in a cluster of majority-CD8+ T cells with high expression of CD69 and FOS. Conclusion: These findings offer insight into the interplay between immune and epithelial cells in EoE. Our data illustrate the relevance of several IFN-γ-mediated mechanisms on epithelial function in the esophagus, which have the potential to impact epithelial function during inflammatory conditions.

Recent Advances in the Treatment of Eosinophilic Esophagitis.

Eosinophilic esophagitis is an increasingly common inflammatory allergic disease of the esophagus characterized by esophageal eosinophilia and symptoms of esophageal dysfunction. The therapeutic landscape has rapidly evolved for this emerging type 2 inflammatory disorder. We review traditional therapies including updates and expert opinions in addition to promising therapies on the horizon and the history of therapies that failed to meet end points and highlight knowledge gaps for future investigations.

Early oral immunotherapy in peanut-allergic preschool children is safe and highly effective.

BACKGROUND: Oral immunotherapy (OIT) is an effective experimental food allergy treatment that is limited by treatment withdrawal and the frequent reversibility of desensitization if interrupted. Newly diagnosed preschool children may have clinical and immunological characteristics more amenable to treatment. OBJECTIVE: We sought to test the safety, effectiveness, and feasibility of early OIT (E-OIT) in the treatment of peanut allergy. METHODS: We enrolled 40 children aged 9 to 36 months with suspected or known peanut allergy. Qualifying subjects reacted to peanut during an entry food challenge and were block-randomized 1:1 to receive E-OIT at goal maintenance doses of 300 or 3000 mg/d in a double-blinded fashion. The primary end point, sustained unresponsiveness at 4 weeks after stopping early intervention oral immunotherapy (4-SU), was assessed by double-blinded, placebo-controlled food challenge either upon achieving 4 prespecified criteria, or after 3 maintenance years. Peanut-specific immune responses were serially analyzed. Outcomes were compared with 154 matched standard-care controls. RESULTS: Of 40 consented subjects, 3 (7.5%) did not qualify. Overall, 29 of 37 (78%) in the intent-to-treat analysis achieved 4-SU (300-mg arm, 17 of 20 [85%]; 3000 mg, 12 of 17 [71%], P = .43) over a median of 29 months. Per-protocol, the overall proportion achieving 4-SU was 29 of 32 (91%). Peanut-specific IgE levels significantly declined in E-OIT-treated children, who were 19 times more likely to successfully consume dietary peanut than matched standard-care controls, in whom peanut-specific IgE levels significantly increased (relative risk, 19.42; 95% CI, 8.7-43.7; P < .001). Allergic side effects during E-OIT were common but all were mild to moderate. CONCLUSIONS: At both doses tested, E-OIT had an acceptable safety profile and was highly successful in rapidly suppressing allergic immune responses and achieving safe dietary reintroduction.

Causes and Outcomes of Esophageal Perforation in Eosinophilic Esophagitis.

GOALS: To characterize patients who suffer perforation in the context of eosinophilic esophagitis (EoE) and to identify predictors of perforation. BACKGROUND: Esophageal perforation is a serious complication of EoE. MATERIALS AND METHODS: We conducted a retrospective cohort study of the University of North Carolina EoE clinicopathologic database from 2001 to 2014. Subjects were included if they had an incident diagnosis of EoE and met consensus guidelines, including nonresponse to a PPI trial. Patients with EoE who had suffered perforation at any point during their course were identified, and compared with EoE cases without perforation. Multiple logistic regression was performed to determine predictors of perforation. RESULTS: Out of 511 subjects with EoE, 10 (2.0%) had experienced an esophageal perforation. Although those who perforated tended to have a longer duration of symptoms before diagnosis (11.4 vs. 7.0 y, P=0.13), a history of food impaction (odds ratio, 14.9; 95% confidence interval, 1.7-129.2) and the presence of a focal stricture (odds ratio, 4.6; 95% confidence interval, 1.1-19.7) were the only factors independently associated with perforation. Most perforations (80%) occurred after a prolonged food bolus impaction, and only half of individuals (5/10) carried a diagnosis of EoE at the time of perforation; none occurred after dilation. Six patients (60%) were treated with nonoperative management, and 4 (40%) required surgical repair. CONCLUSIONS: Esophageal perforation is a rare but serious complication of eosinophilic esophagitis, occurring in ∼2% of cases. Most episodes are due to food bolus impaction or strictures, suggesting that patients with fibrostenotic disease due to longer duration of symptoms are at increased risk.

Management of Eosinophilic Esophagitis During Pregnancy.

There are currently limited data on the management of eosinophilic esophagitis (EoE) during pregnancy. At our center, however, we have followed several pregnant women with EoE and others have asked pertinent questions in pre-pregnancy counseling. The relatively young age of patients with EoE implies that many practitioners will also encounter patients with these questions. In this review, we use four cases to prompt a discussion about concerns focused on the safety of steroids and diet therapy during pregnancy and breast-feeding, potential nutritional risks with dietary elimination, how to optimize therapy, and whether endoscopic evaluation for monitoring of disease activity is safe during pregnancy and breast-feeding. An additional concern is whether the disease could progress during pregnancy and breast-feeding if no therapies are used. Although there are no studies specifically examining pregnant EoE patients, we have reviewed the literature relevant to this population as informed by the treatment of inflammatory bowel disease patients during pregnancy, where these issues have been studied in more depth. Providers who care for EoE patients who could become pregnant should familiarize themselves with these issues.

Outcomes of Esophageal Dilation in Eosinophilic Esophagitis: Safety, Efficacy, and Persistence of the Fibrostenotic Phenotype.

OBJECTIVES: Esophageal dilation is commonly performed in eosinophilic esophagitis (EoE), but there are few long-term data. The aims of this study were to assess the safety and long-term efficacy of esophageal dilation in a large cohort of EoE cases, and to determine the frequency and predictors of requiring multiple dilations. METHODS: We conducted a retrospective cohort study in the University of North Carolina EoE Clinicopathological Database from 2002 to 2014. Included subjects met consensus diagnostic criteria for EoE. Clinical, endoscopic, and histologic features were extracted, as were dilation characteristics (dilator type, change in esophageal caliber, and total number of dilations) and complications. Patients with EoE who had undergone dilation were compared with those who did not and also stratified by whether they required single or multiple dilations. RESULTS: Of 509 EoE patients, 164 were dilated a total of 486 times. Those who underwent dilation had a longer duration of symptoms before diagnosis (11.1 vs. 5.4 years, P<0.001). Ninety-five patients (58%) required >1 dilation (417 dilations total, mean of 4.4±4.3 per patient). The only predictor of requiring multiple dilations was a smaller baseline esophageal diameter. Dilation was tolerated well, with no major bleeds, perforations, or deaths. The overall complication rate was 5%, primarily due to post-procedural pain. Of 164 individuals dilated, a majority (58% or 95/164) required a second dilation. Of these individuals, 75% required repeat dilation within 1 year. CONCLUSIONS: Dilation in EoE is well-tolerated, with a very low risk of serious complications. Patients with long-standing symptoms before diagnosis are likely to require dilation. More than half of those dilated will require multiple dilations, often needing a second procedure within 1 year. These findings can be used to counsel patients with fibrostenotic complications of EoE.

The extremely narrow-caliber esophagus is a treatment-resistant subphenotype of eosinophilic esophagitis.

BACKGROUND AND AIMS: Some patients with eosinophilic esophagitis (EoE) have an extremely narrow esophagus, but the characteristics of this group have not been extensively described. We aimed to characterize the narrow-caliber phenotype of EoE, determine associated risk factors, and identify differences in treatment response in this subgroup of patients. METHODS: This retrospective cohort study from 2001 to 2014 included subjects with a new diagnosis of EoE per consensus guidelines. Demographic, endoscopic, histologic, and treatment response data were extracted from medical records. An extremely narrow-caliber esophagus was defined when a neonatal endoscope was required to traverse the esophagus due to the inability to pass an adult endoscope. Patients with and without an extremely narrow-caliber esophagus were compared. Multivariable logistical regression was performed to assess treatment outcomes. RESULTS: Of 513 patients with EoE, 46 (9%) had an extremely narrow-caliber esophagus. These patients were older (33 vs 22 years; P < .01), had longer symptom duration (11 vs 3 years; P < .01), more dysphagia (98% vs 66%; P < .01), and food impactions (53% vs 31%; P < .01). Dilation was more common with extreme narrowing (69% vs 17%; P < .01). Patients with a narrow-caliber esophagus were more refractory to steroid treatment, with lower symptom (56% vs 85%), endoscopic (52% vs 76%), and histologic (33% vs 63%) responses (P < .01 for all), and these differences persisted after multivariate analysis. CONCLUSION: The extremely narrow-caliber esophagus is a more treatment-resistant subphenotype of EoE and is characterized by longer symptom duration and the need for multiple dilations. Recognition of an extremely narrow-caliber esophagus at diagnosis of EoE can provide important prognostic information.

Strategies to mitigate peanut allergy: production, processing, utilization, and immunotherapy considerations.

Peanut (Arachis hypogaea L.) is an important crop grown worldwide for food and edible oil. The surge of peanut allergy in the past 25 years has profoundly impacted both affected individuals and the peanut and related food industries. In response, several strategies to mitigate peanut allergy have emerged to reduce/eliminate the allergenicity of peanuts or to better treat peanut-allergic individuals. In this review, we give an overview of peanut allergy, with a focus on peanut proteins, including the impact of thermal processing on peanut protein structure and detection in food matrices. We discuss several strategies currently being investigated to mitigate peanut allergy, including genetic engineering, novel processing strategies, and immunotherapy in terms of mechanisms, recent research, and limitations. All strategies are discussed with considerations for both peanut-allergic individuals and the numerous industries/government agencies involved throughout peanut production and utilization.