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The Consortium of Eosinophilic Gastrointestinal disease Researchers (CEGIR) and The International Gastrointestinal Eosinophil Researchers (TIGERS) organized a day-long symposium at the 2024 Annual Meeting of the American Academy of Allergy, Asthma & Immunology. The symposium featured new discoveries in basic and translational research and debates on the mechanisms and management of eosinophilic gastrointestinal diseases (EGIDs). Updates on recent clinical trials and consensus guidelines were also presented. Herein, we summarize the updates on EGIDs presented at the symposium.
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Anticuerpos Monoclonales Humanizados , Esofagitis Eosinofílica , Animales , Humanos , Esofagitis Eosinofílica/diagnóstico , Esofagitis Eosinofílica/tratamiento farmacológico , Esofagitis Eosinofílica/inmunología , Esofagitis Eosinofílica/patología , Eosinófilos/inmunología , Eosinófilos/patología , Esófago/efectos de los fármacos , Esófago/inmunología , Esófago/patología , Niño , Adulto , Adolescente , Anticuerpos Monoclonales Humanizados/uso terapéutico , Ensayos Clínicos Controlados Aleatorios como AsuntoRESUMEN
Background: The demographic characteristics of patients with eosinophilic gastrointestinal diseases (EGIDs) are poorly understood. Population-based assessments of EGID demographics may indicate health disparities in diagnosis. Objectives: We aimed to characterize the demographic distribution of EGIDs and evaluate the potential for bias in reporting patient characteristics. Methods: We conducted a systematic review, extracting data on age, sex, gender, race, ethnicity, body mass index, insurance, and urban/rural residence on EGID patients and the source population. Differences in proportions were assessed by chi-square tests. Demographic reporting was compared to recent guidelines. Results: Among 50 studies that met inclusion/exclusion criteria, 12 reported ≥1 demographic feature in both EGID and source populations. Except for age and sex or gender, demographics were rarely described (race = 4, ethnicity = 1, insurance = 1) or were not described (body mass index, urban/rural residence). A higher proportion of male subjects was observed for EoE or esophageal eosinophilia relative to the source population, but no difference in gender or sex distribution was observed for other EGIDs. "Sex" and "gender" were used interchangeably, and frequently only the male proportion was reported. Reporting of race and ethnicity was inconsistent with guidelines. Conclusion: Current data support a male predominance for EoE only. Evidence was insufficient to support enrichment of EGIDs in any particular racial, ethnic, or other demographic group. Population-based studies presenting demographics on both cases and source populations are needed. Implementation of guidelines for more inclusive reporting of demographic characteristics is crucial to prevent disparities in timely diagnosis and management of patients with EGIDs.
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Immunotherapy is a treatment approach based on the principle of incremental allergen exposure to achieve desensitization. Recently, oral immunotherapy has been introduced as a treatment of IgE-mediated food allergy. Some patients receiving oral immunotherapy for food allergy may develop eosinophilic esophagitis. Here, we summarize the literature examining this association, its treatment, and outcomes and discuss possible explanations for this clinical phenomenon. We further identify potential associations with aeroallergen sensitivity and other forms of immunotherapy including subcutaneous immunotherapy and sublingual immunotherapy. Finally, we discuss management of immunotherapy-induced eosinophilic esophagitis. Epicutaneous immunotherapy is highlighted as an area of therapeutic investigation.
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Esofagitis Eosinofílica , Hipersensibilidad a los Alimentos , Inmunoterapia Sublingual , Humanos , Esofagitis Eosinofílica/etiología , Esofagitis Eosinofílica/terapia , Desensibilización Inmunológica/efectos adversos , Hipersensibilidad a los Alimentos/tratamiento farmacológico , Alérgenos/uso terapéuticoRESUMEN
Introduction: Eosinophilic esophagitis (EoE) is a chronic, inflammatory, antigen-driven disease of the esophagus. Tissue EoE pathology has previously been extensively characterized by novel transcriptomics and proteomic platforms, however the majority of surface marker determination and screening has been performed in blood due to mucosal tissue size limitations. While eosinophils, CD4+ T cells, mast cells and natural killer (NK) T cells were previously investigated in the context of EoE, an accurate picture of the composition of peripheral blood mononuclear cells (PBMC) and their activation is missing. Methods: In this study, we aimed to comprehensively analyze the composition of peripheral blood mononuclear cells and their activation using surface marker measurements with multicolor flow cytometry simultaneously in both blood and mucosal tissue of patients with active EoE, inactive EoE, patients with gastroesophageal reflux disease (GERD) and controls. Moreover, we set out to validate our data in co-cultures of PBMC with human primary esophageal epithelial cells and in a novel inducible mouse model of eosinophilic esophagitis, characterized by extensive IL-33 secretion in the esophagus. Results: Our results indicate that specific PBMC populations are enriched, and that they alter their surface expression of activation markers in mucosal tissue of active EoE. In particular, we observed upregulation of the immunomodulatory molecule CD38 on CD4+ T cells and on myeloid cells in biopsies of active EoE. Moreover, we observed significant upregulation of PD-1 on CD4+ and myeloid cells, which was even more prominent after corticosteroid treatment. With co-culture experiments we could demonstrate that direct cell contact is needed for PD-1 upregulation on CD4+ T cells. Finally, we validated our findings of PD-1 and CD38 upregulation in an inducible mouse model of EoE. Discussion: Herein we show significant alterations in the PBMC activation profile of patients with active EoE in comparison to inactive EoE, GERD and controls, which could have potential implications for treatment. To our knowledge, this study is the first of its kind expanding the multi-color flow cytometry approach in different patient groups using in vitro and in vivo translational models.
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Enteritis , Eosinofilia , Esofagitis Eosinofílica , Gastritis , Reflujo Gastroesofágico , Animales , Ratones , Humanos , Esofagitis Eosinofílica/diagnóstico , Leucocitos Mononucleares/metabolismo , Receptor de Muerte Celular Programada 1 , Proteómica , Membrana Mucosa/metabolismo , Reflujo Gastroesofágico/diagnóstico , Reflujo Gastroesofágico/patologíaRESUMEN
BACKGROUND: Eosinophilic esophagitis (EoE) is an increasingly common inflammatory condition of the esophagus; however, the underlying immunologic mechanisms remain poorly understood. The epithelium-derived cytokine IL-33 is associated with type 2 immune responses and elevated in esophageal biopsy specimens from patients with EoE. OBJECTIVE: We hypothesized that overexpression of IL-33 by the esophageal epithelium would promote the immunopathology of EoE. METHODS: We evaluated the functional consequences of esophageal epithelial overexpression of a secreted and active form of IL-33 in a novel transgenic mouse, EoE33. EoE33 mice were analyzed for clinical and immunologic phenotypes. Esophageal contractility was assessed. Epithelial cytokine responses were analyzed in three-dimensional organoids. EoE33 phenotypes were further characterized in ST2-/-, eosinophil-deficient, and IL-13-/- mice. Finally, EoE33 mice were treated with dexamethasone. RESULTS: EoE33 mice displayed ST2-dependent, EoE-like pathology and failed to thrive. Esophageal tissue remodeling and inflammation included basal zone hyperplasia, eosinophilia, mast cells, and TH2 cells. Marked increases in levels of type 2 cytokines, including IL-13, and molecules associated with immune responses and tissue remodeling were observed. Esophageal organoids suggested reactive epithelial changes. Genetic deletion of IL-13 in EoE33 mice abrogated pathologic changes in vivo. EoE33 mice were responsive to steroids. CONCLUSIONS: IL-33 overexpression by the esophageal epithelium generated immunopathology and clinical phenotypes resembling human EoE. IL-33 may play a pivotal role in the etiology of EoE by activating the IL-13 pathway. EoE33 mice are a robust experimental platform for mechanistic investigation and translational discovery.
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Esofagitis Eosinofílica , Interleucina-13 , Interleucina-33 , Animales , Humanos , Ratones , Modelos Animales de Enfermedad , Esofagitis Eosinofílica/inmunología , Esofagitis Eosinofílica/genética , Esofagitis Eosinofílica/patología , Eosinófilos/inmunología , Mucosa Esofágica/patología , Mucosa Esofágica/inmunología , Esófago/patología , Esófago/inmunología , Proteína 1 Similar al Receptor de Interleucina-1/genética , Proteína 1 Similar al Receptor de Interleucina-1/metabolismo , Interleucina-13/genética , Interleucina-13/inmunología , Interleucina-13/metabolismo , Interleucina-33/genética , Interleucina-33/inmunología , Interleucina-33/metabolismo , Ratones Endogámicos C57BL , Ratones Noqueados , Ratones TransgénicosRESUMEN
Although eosinophilic gastrointestinal diseases, including eosinophilic esophagitis, have been described over the past 2 to 3 decades, barriers to diagnosis and treatment are common and compounded by issues related to social determinants of health, race, ethnicity, and access to care. These barriers contribute to delays in diagnosis, resulting in persistent inflammation in the gastrointestinal tract, which can have significant consequences, including fibrostenotic complications in adults, failure to thrive in children, and decreased quality of life in all affected patients. In this commentary, we summarize gaps in knowledge regarding the epidemiology of eosinophilic gastrointestinal diseases, highlight barriers to diagnosis, discuss potential approaches based on best practices in other atopic and chronic gastrointestinal diseases, and provide recommendations for reducing barriers to timely diagnosis of eosinophilic gastrointestinal diseases in underserved populations.
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Enteritis , Eosinofilia , Esofagitis Eosinofílica , Gastritis , Adulto , Niño , Humanos , Calidad de Vida , Enteritis/diagnóstico , Enteritis/epidemiología , Enteritis/terapia , Gastritis/diagnóstico , Gastritis/epidemiología , Gastritis/terapia , Esofagitis Eosinofílica/diagnóstico , Esofagitis Eosinofílica/epidemiología , Esofagitis Eosinofílica/terapiaRESUMEN
The Consortium of Eosinophilic Gastrointestinal Diseases and The International Gastrointestinal Eosinophil Researchers organized a day-long symposium at the 2022 Annual Meeting of the American Academy of Allergy, Asthma & Immunology. The symposium featured a review of recent discoveries in the basic biology and pathogenesis of eosinophilic gastrointestinal diseases (EGIDs) in addition to advances in our understanding of the clinical features of EGIDs. Diagnostic and management approaches were reviewed and debated, and clinical trials of emerging therapies were highlighted. Herein, we briefly summarize the breakthrough discoveries in EGIDs.
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Asma , Enteritis , Eosinofilia , Esofagitis Eosinofílica , Gastritis , Humanos , Estados Unidos , Enteritis/diagnóstico , Enteritis/terapia , Asma/diagnóstico , Asma/terapiaRESUMEN
In response to the social inequities that exist in health care, the NIH-funded Consortium of Eosinophilic Gastrointestinal Disease Researchers (CEGIR) recently formed a diversity committee to examine systemic racism and implicit bias in the care and research of eosinophilic gastrointestinal diseases (EGIDs). Herein, we describe our process, highlighting milestones and issues addressed since the committee's inception, which we hope will inspire other researchers to enhance diversity, equity, inclusion, and accessibility (DEIA) in their fields. Our journey began by establishing mission and vision statements to define the purpose of the committee. Regular discussion of diversity-related topics was incorporated into existing meetings and web-based materials were shared. This was followed by educational initiatives, including establishing a library of relevant publications and a speaker series to address DEIA topics. We then established a research agenda focused on the following actionable items: (1) to define what is known about the demographics of EGIDs by systematic review of population-based studies; (2) to develop a practical tool for reporting participant demographics to reduce bias in EGID literature; (3) to examine health disparities in the care of individuals with eosinophilic esophagitis who present to the emergency department with an esophageal food impaction; (4) to examine how access to a gastroenterologist affects the conclusions of published research examining the prevalence of pediatric eosinophilic esophagitis; and (5) to develop a model for examining the dimensions of diversity, and provide a framework for CEGIR's ongoing projects and data capture. In addition to promoting consciousness of DEIA, this initiative has fostered inclusivity among CEGIR members and will continue to inspire positive changes in EGID care and research.
Diversity in Eosinophilic Gastrointestinal Disease Research To address systemic bias in patient care and research in eosinophilic gastrointestinal diseases, the Consortium of Eosinophilic Gastrointestinal Disease Researchers (CEGIR) recently formed a diversity committee. The CEGIR diversity committee has defined its purpose through mission and vision statements and developed structured educational and research initiatives to enhance diversity, equity, inclusivity, and accessibility (DEIA) in all CEGIR activities. Here, we share the process of formation of our diversity committee, highlighting milestones achieved and summarizing future directions. We hope that this report will serve as a guide and an inspiration for other researchers to enhance DEIA in their fields.
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Eosinophilic esophagitis (EoE) is a chronic allergic inflammatory disease requiring maintenance therapy. Traditionally, EoE has been a contraindication to oral immunotherapy (OIT) and a rationale for discontinuing treatment because OIT may induce EoE. Most, but not all patients with OIT-induced EoE experience symptom resolution and histologic remission after discontinuing OIT. Recent studies report OIT continuation even after EoE onset, despite the previously accepted standard of care. This creates clinical as well as ethical challenges for allergists treating these patients. Considering the published literature on EoE and OIT and the primary medical ethics principles of beneficence, nonmaleficence, autonomy, and justice, we discuss the ethical implications of pursuing desensitization despite the potential complications associated with EoE. When ethical principles are in opposition, shared decision-making should be employed to determine whether OIT should be continued after an EoE diagnosis. This article highlights the ethical dilemmas allergists face when determining whether patients with a diagnosis of EoE should continue OIT.
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Enteritis , Esofagitis Eosinofílica , Gastritis , Humanos , Esofagitis Eosinofílica/terapia , Esofagitis Eosinofílica/etiología , Gastritis/complicaciones , Enteritis/complicaciones , Inmunoterapia/efectos adversosRESUMEN
BACKGROUND: Basal zone hyperplasia (BZH) and dilated intercellular spaces (DISs) are thought to contribute to the clinical manifestations of eosinophilic esophagitis (EoE); however, the molecular pathways that drive BZH remain largely unexplored. OBJECTIVE: We sought to define the role of IL-13-induced transcriptional programs in esophageal epithelial proliferation in EoE. METHODS: We performed RNA sequencing, bioinformatics, Western blot, reverse transcriptase quantitative PCR, and histologic analyses on esophageal biopsies from healthy control and patients with EoE, primary esophageal cells derived from patients with EoE, and IL-13-stimulated esophageal epithelial keratinocytes grown at the air-liquid interface (EPC2-ALI). Genetic (shRNA) and pharmacologic (proteolysis-targeting chimera degrader) approaches and in vivo model of IL-13-induced esophageal epithelial remodeling (Krt5-rtTA x tetO-IL-13Tg) were used to define the role of signal transducer and activator of transcription 3 (STAT3) and STAT6 and secreted frizzled-related protein 1 (SFRP1) in esophageal epithelial proliferation. RESULTS: RNA-sequencing analysis of esophageal biopsies (healthy control vs EoE) and EPC2-ALI revealed 82 common differentially expressed genes that were enriched for putative STAT3 target genes. In vitro and in vivo analyses revealed a link between IL-13-induced STAT3 and STAT6 phosphorylation, SFRP1 mRNA expression, and esophageal epithelial proliferation. In vitro studies showed that IL-13-induced esophageal epithelial proliferation was STAT3-dependent and regulated by the STAT3 target SFRP1. SFRP1 mRNA is increased in esophageal biopsies from patients with active EoE compared with healthy controls or patients in remission and identifies an esophageal suprabasal epithelial cell subpopulation that uniquely expressed the core EoE proinflammatory transcriptome genes (CCL26, ALOX15, CAPN14, ANO1, and TNFAIP6). CONCLUSIONS: These studies identify SFRP1 as a key regulator of IL-13-induced and STAT3-dependent esophageal proliferation and BZH in EoE and link SFRP1+ esophageal epithelial cells with the proinflammatory and epithelial remodeling response in EoE.
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Esofagitis Eosinofílica , Humanos , Esofagitis Eosinofílica/patología , Interleucina-13/metabolismo , Factor de Transcripción STAT3/genética , Factor de Transcripción STAT3/metabolismo , Células Epiteliales/metabolismo , ARN Mensajero/metabolismo , Proliferación CelularRESUMEN
Despite the high incidence of COVID-19 worldwide, clinical experience with severe acute respiratory syndrome coronavirus 2 (SARS-COV-2) in inborn errors of immunity remains limited. Recent studies have shown that patients with defects in type 1 interferon (IFN)-related pathways or those with autoantibodies against type 1 IFNs develop severe COVID-19. We reported the clinical course of 22 patients with CTLA-4 insufficiency and COVID-19 and retrospectively examined autoantibodies against type 1 IFNs at baseline. Data were obtained from the patient interviews and chart reviews. Screening for anti-IFN autoantibodies was performed using a multiplex particle-based assay. Student t test, Mann Whitney, analysis of variance, or χ2 tests were used where appropriate. Twenty-two patients aged from 8 months to 54 years, with genetically confirmed CLTA-4 insufficiency, developed COVID-19 from 2020 to 2022. The most common symptoms were fever, cough, and nasal congestion, and the median duration of illness was 7.5 days. Twenty patients (91%) developed mild COVID-19 and were treated as outpatients. Two patients were hospitalized because of COVID-19 pneumonia but did not require mechanical ventilation. Ten (45%) patients were vaccinated at the time of their first COVID-19 infection. Eleven patients received outpatient treatment with monoclonal antibodies against the SARS-CoV-2 spike protein. During the study period, 17 patients were vaccinated against SARS-CoV-2, with no severe vaccine-related adverse effects. Although median anti-S titers following vaccination or infection were lower in patients receiving immunoglobulin replacement therapy (IGRT) (349 IU/dL) than in those not receiving IGRT (2594 IU/dL; P = .15); 3 of 9 patients on IGRT developed titers >2000 IU/dL. All patients tested negative for autoantibodies against IFN-α, IFN-ß, and IFN-ω at baseline. Most patients with CTLA-4 insufficiency and COVID-19 had nonsevere disease, lacked autoantibodies against type 1 IFNs, and tolerated messenger RNA vaccines with few adverse effects. Whether our findings can be extrapolated to patients receiving CTLA-4-targeting checkpoint inhibitors requires further studies.
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COVID-19 , Humanos , Autoanticuerpos , Antígeno CTLA-4 , Estudios Retrospectivos , SARS-CoV-2RESUMEN
PURPOSE OF REVIEW: The prevalence and incidence of allergic disease have been rising in Westernized countries since the twentieth century. Increasingly, evidence suggests that damage to the epithelium initiates and shapes innate and adaptive immune responses to external antigens. The objective of this review is to examine the role of detergents as a potential risk factor for developing allergic disease. RECENT FINDINGS: Herein, we identify key sources of human detergent exposure. We summarize the evidence suggesting a possible role for detergents and related chemicals in initiating epithelial barrier dysfunction and allergic inflammation. We primarily focus on experimental models of atopic dermatitis, asthma, and eosinophilic esophagitis, which show compelling associations between allergic disease and detergent exposure. Mechanistic studies suggest that detergents disrupt epithelial barrier integrity through their effects on tight junction or adhesion molecules and promote inflammation through epithelial alarmin release. Environmental exposures that disrupt or damage the epithelium may account for the increasing rates of allergic disease in genetically susceptible individuals. Detergents and related chemical compounds represent possible modifiable risk factors for the development or exacerbation of atopy.
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Asma , Dermatitis Atópica , Esofagitis Eosinofílica , Humanos , Detergentes/efectos adversos , InflamaciónRESUMEN
BACKGROUND: Group 2 innate lymphoid cells (ILC2s) are critical mediators of type 2 respiratory inflammation, releasing IL-5 and IL-13 and promoting the pulmonary eosinophilia associated with allergen provocation. Although ILC2s have been shown to promote eosinophil activities, the role of eosinophils in group 2 innate lymphoid cell (ILC2) responses is less well defined. OBJECTIVE: We sought to investigate the role of eosinophils in activation of ILC2s in models of allergic asthma and in vitro. METHODS: Inducible eosinophil-deficient mice were exposed to allergic respiratory inflammation models of asthma, such as ovalbumin or house dust mite challenge, or to innate models of type 2 airway inflammation, such as inhalation of IL-33. Eosinophil-specific IL-4/13-deficient mice were used to address the specific roles for eosinophil-derived cytokines. Direct cell interactions between ILC2s and eosinophils were assessed by in vitro culture experiments. RESULTS: Targeted depletion of eosinophils resulted in significant reductions of total and IL-5+ and IL-13+ lung ILC2s in all models of respiratory inflammation. This correlated with reductions in IL-13 levels and mucus in the airway. Eosinophil-derived IL-4/13 was necessary for both eosinophil and ILC2 accumulation in lung in allergen models. In vitro, eosinophils released soluble mediators that induced ILC2 proliferation and G protein-coupled receptor-dependent chemotaxis of ILC2s. Coculture of ILC2s and IL-33-activated eosinophils resulted in transcriptome changes in both ILC2s and eosinophils, suggesting potential novel reciprocal interactions. CONCLUSION: These studies demonstrate that eosinophils play a reciprocal role in ILC2 effector functions as part of both adaptive and innate type 2 pulmonary inflammatory events.
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Asma , Inmunidad Innata , Ratones , Animales , Eosinófilos/metabolismo , Interleucina-33/metabolismo , Interleucina-13/metabolismo , Interleucina-5/metabolismo , Interleucina-4/metabolismo , Linfocitos , Pulmón , Citocinas/metabolismo , Asma/metabolismo , Inflamación/metabolismo , Alérgenos/metabolismoRESUMEN
Continuing insight into the molecular mechanisms of atopic disorders has enabled the development of biologics to precisely target these diseases. Food allergy (FA) and eosinophilic gastrointestinal disorders (EGIDs) are driven by similar inflammatory molecular mechanisms and exist along the same atopic disease spectrum. Therefore, many of the same biologics are being investigated to target key drivers of mechanisms shared across the disease states. The enormous potential of biologics for the treatment of FA and EGIDs is highlighted by the significant increases in the number of ongoing clinical trials (more than 30) evaluating their use in these disease states, as well as by the recent US Food and Drug Administration approval of dupilumab for the treatment of eosinophilic esophagitis. Here we discuss past and current research into the use of biologics in FA and EGIDs and their potential role in improving treatment options in the future, with the need to have biologics widely clinically available.
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Productos Biológicos , Enteritis , Esofagitis Eosinofílica , Hipersensibilidad a los Alimentos , Estados Unidos , Humanos , NiñoRESUMEN
BACKGROUND: Food-specific immunoglobulin G4 (FS-IgG4) is associated with eosinophilic esophagitis (EoE); however, it is not clear whether production is limited to the esophagus. AIMS: To assess FS-IgG4 levels in the upper gastrointestinal tract and plasma and compare these with endoscopic disease severity, tissue eosinophil counts, and patient-reported symptoms. METHODS: We examined prospectively banked plasma, throat swabs, and upper gastrointestinal biopsies (esophagus, gastric antrum, and duodenum) from control (n = 15), active EoE (n = 24), and inactive EoE (n = 8) subjects undergoing upper endoscopy. Patient-reported symptoms were assessed using the EoE symptom activity index (EEsAI). Endoscopic findings were evaluated using the EoE endoscopic reference score (EREFS). Peak eosinophils per high-power field (eos/hpf) were assessed from esophageal biopsies. Biopsy homogenates and throat swabs were normalized for protein content and assessed for FS-IgG4 to milk, wheat, and egg. RESULTS: Median FS-IgG4 for milk and wheat was significantly increased in the plasma, throat swabs, esophagus, stomach, and duodenum of active EoE subjects compared to controls. No significant differences for milk- or wheat-IgG4 were observed between active and inactive EoE subjects. Among the gastrointestinal sites sampled, FS-IgG4 levels were highest in the esophagus. Esophageal FS-IgG4 for all foods correlated significantly across all sites sampled (r ≥ 0.59, p < 0.05). Among subjects with EoE, esophageal FS-IgG4 correlated significantly with peak eos/hpf (milk and wheat) and total EREFS (milk). EEsAI scores and esophageal FS-IgG4 levels did not correlate. CONCLUSIONS: Milk and wheat FS-IgG4 levels are elevated in plasma and throughout the upper gastrointestinal tract in EoE subjects and correlate with endoscopic findings and esophageal eosinophilia.
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Esofagitis Eosinofílica , Hipersensibilidad a los Alimentos , Inmunoglobulina G , Tracto Gastrointestinal Superior , Humanos , Inmunoglobulina G/sangre , Estudios Prospectivos , Estudios de Casos y Controles , Eosinófilos , Endoscopía Gastrointestinal , Biomarcadores , Tracto Gastrointestinal Superior/metabolismo , Masculino , Femenino , Adulto , Persona de Mediana Edad , AncianoRESUMEN
BACKGROUND: Eosinophilic esophagitis (EoE) is a chronic allergic disease associated with type 2 inflammation and epithelial barrier dysfunction. The etiology is unknown, however, genetic heritability studies suggest environmental factors play a key role in pathogenesis. Detergents, such as sodium dodecyl sulfate (SDS), are common ingredients in household products such as dish soap and toothpaste. We hypothesized detergent exposure decreases epithelial barrier function and induces esophageal inflammation. METHODS: Immortalized esophageal epithelial cells (EPC2) were cultured in air-liquid interface (ALI) and exposed to SDS. Barrier function/activity was assessed by transepithelial electrical resistance (TEER), FITC-dextran flux, and RT-PCR. Additionally, SDS-treated mouse esophageal organoids were evaluated for morphology. To investigate the effects of SDS in vivo, mice were treated with 0.5% SDS in drinking water for 14 days. Esophagi were assessed by gross morphology, histopathology, protein expression, and bulk RNA sequencing. RESULTS: When EPC2 cells were exposed to SDS (5 µg/ml) for 96 h, TEER decreased (p = 0.03), and FITC-dextran flux increased (p = 0.0002). mRNA expression of IL-33 increased 4.5-fold (p = 0.02) at 6 h and DSG1 decreased (p < 0.0001) by 72 h. Disrupted epithelial integrity was noted in SDS-treated esophageal organoids. When mice were exposed to SDS, they showed increased esophageal width, chemokine, and metalloprotease levels. Mice treated with SDS also showed increased IL-33 protein expression, basal zone hyperplasia, CD4+ cell infiltration, and esophageal eosinophilia. RNA sequencing revealed upregulation of immune response pathway genes. CONCLUSION: Exposure to SDS decreases esophageal barrier integrity, stimulates IL-33 production, and promotes epithelial hyperplasia and tissue eosinophilia. Detergents may be a key environmental trigger in EoE pathogenesis.
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Detergentes , Esofagitis Eosinofílica , Animales , Ratones , Detergentes/efectos adversos , Células Epiteliales/metabolismo , Hiperplasia/patología , Inflamación/metabolismo , Interleucina-33/metabolismoRESUMEN
Eosinophilic esophagitis (EoE) is a chronic allergy-mediated condition with an increasing incidence in both children and adults. Despite EoE's strong impact on human health and welfare, there is a large unmet need for treatments with only one recently FDA-approved medication for EoE. The goal of this study was to establish swine as a relevant large animal model for translational biomedical research in EoE with the potential to facilitate development of therapeutics. We recently showed that after intraperitoneal sensitization and oral challenge with the food allergen hen egg white protein (HEWP), swine develop esophageal eosinophilia-a hallmark of human EoE. Herein, we used a similar sensitization and challenge treatment and evaluated immunological and pathological markers associated with human EoE. Our data demonstrate that the incorporated sensitization and challenge treatment induces (i) a systemic T-helper 2 and IgE response, (ii) a local expression of eotaxin-1 and other allergy-related immune markers, (iii) esophageal eosinophilia (>15â eosinophils/0.24â mm2), and (iv) esophageal endoscopic findings including linear furrows and white exudates. Thereby, we demonstrate that our sensitization and oral challenge protocol not only induces the underlying immune markers but also the micro- and macro-pathological hallmarks of human EoE. This swine model for EoE represents a novel relevant large animal model that can drive translational biomedical research to develop urgently needed treatment strategies for EoE.