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Penetration of the Esophageal Epithelium by Dust Mite Antigen in Patients With Eosinophilic Esophagitis

2019; Elsevier BV; Volume: 157; Issue: 1 Linguagem: Inglês

10.1053/j.gastro.2019.02.042

1528-0012

Anupama Ravi, Eric Marietta, Debra M. Geno, Jeffrey A. Alexander, Joseph A. Murray, David A. Katzka,

Eosinophilic Disorders and Syndromes

See editorial on page 17. See editorial on page 17. Although eosinophilic esophagitis (EoE) is a food antigen–driven Th-2 allergic disease, there is evidence that environmental allergies may modulate disease activity.1Jensen E.T. et al.Aliment Pharmacol Ther. 2015; 42: 461-469Crossref PubMed Scopus (45) Google Scholar For example, animal models that recapitulate EoE are achieved through initial epicutaneous exposure to ovalbumin or respiratory exposure to aspergillus fumigates or dust mite antigen.2O'Shea K.M. et al.Gastroenterology. 2018; 154: 333-345Abstract Full Text Full Text PDF PubMed Scopus (199) Google Scholar, 3Rayapudi M. et al.J Leukoc Biol. 2010; 88: 337-346Crossref PubMed Scopus (82) Google Scholar On the other hand, aeroallergens are incidentally ingested in addition to inhaled. We have demonstrated the presence of ingested gluten in the esophageal epithelium of patients with EoE, suggesting that penetration of ingested antigen occurs.4Marietta E.V. et al.Aliment Pharmacol Ther. 2017; 45: 427-433Crossref PubMed Scopus (25) Google Scholar In this study, we aimed to detect the presence of dust mite antigen, a perennial and common cause of environmental allergy, in patients with EoE. Three groups of patients were studied: active EoE, inactive EoE, and control patients all undergoing clinically indicated endoscopy without a history of esophageal disease or symptoms. EoE was defined by esophageal eosinophilia >15 per high power field and presence of dysphagia per consensus guidelines.5Dellon E.S. et al.Am J Gastroenterol. 2013; 108 (quiz 693): 679-692Crossref PubMed Scopus (803) Google Scholar Patients with inactive EoE had <15 eosinophils/high power field. Patients undergoing clinically indicated endoscopy had extra biopsies taken in part for dust mite allergen. Patients were excluded if strictures precluded passage of the endoscope. Biopsies were placed in Optimal Cutting Temperature compound and snap frozen on dry ice followed by cryosectioning. Dust mite (DF10) staining was performed (Novus Biologicals Purified anti–House Dust Mite. Cat#NB110–2605 Anti-Mouse immunoglobulin [Ig]G: Jackson ImmunoResearch Laboratories, West Grove, PA). Rhodamine red was used as the secondary antibody (Rhodamine Red-X Conjugated Donkey anti-Mouse IgG cat#715–296–151, Jackson ImmunoResearch Laboratories); 4′,6-diamidino-2-phenylindole stain was used to counterstain nuclei. Grading of positive dust mite staining was performed (0–4 scale of percentage of microscopic field: 1 = 1%–25%, 2 = 26%–50%, 3 = 51%–75%, 4 = >75%, ×63 magnification). Staining intensity (1 = dim, 2 = bright) and number of discreet deposits (sites) of staining also were assessed. Analysis of routine histology taken at the time of biopsy was assessed for eosinophil count. This study was approved by the institutional review board of the Mayo Clinic. Mann-Whitney testing and nonparametric testing were used. There were 7 patients in each EoE group. Patients with EoE were a mean of 39.9 years old (range 18 to 56), 3 were male, and all were white. Only 2 patients underwent radioallergosorbent test and/or skin testing at Mayo and 1 had allergy to dust mites. Of the 14 patients, 5 had allergic rhinitis, 4 had oral allergy syndrome to food, 4 had hives, 2 had eczema, and 1 had asthma. For active patients, eosinophil count was 66.4 (range 20 to >100). Endoscopic EoE reference score was 4 ± 1. Inactive patients had mean 0.86 eos (range 0 to 4) with lower EoE reference score 1 ± 1, P = .011. Control patients were a mean age of 51.3 (range 23–67), all were white, and 3 were male and had normal-appearing endoscopy and histology without evidence of esophageal eosinophilia. Active patients had dust mite staining %field 1.6 ± 1.3, which was significantly greater than inactive patients (0.7 ± 0.4, P = .0217) (Figure 1). Active patients had 10.7 ± 12.5 sites of staining compared with 2.0 ± 2.1 for inactive (P < .001). Field staining intensity was 1.5 ± 0.7 active vs. 1.1 (P = NS). Dilation of intercellular spaces was present in 6 of 7 active EoE, 3 of 7 inactive EoE, and no control patients. Control patients without esophageal disease demonstrated a complete absence of epithelial dust mite antigen staining. One of the possible mechanisms by which food antigens initiate activity in EoE is thought to be by penetration through a perturbed esophageal epithelial barrier, recognition by an antigen-presenting cell in the mucosa, and activation of disease through activation of cellular and cytokine-mediated pathways.2O'Shea K.M. et al.Gastroenterology. 2018; 154: 333-345Abstract Full Text Full Text PDF PubMed Scopus (199) Google Scholar This mechanism is strongly suggested not only by the inflammatory pathways initiated by epithelial antigen exposure, but more recently by documenting the presence of gluten in esophageal epithelium of patients with active but less so inactive EoE. On the other hand, activation of EoE by aeroallergens is thought to occur through a systemic priming mechanism involving eosinophil trafficking to the esophagus from the respiratory tree and bone marrow.6Rajavelu P. et al.Am J Physiol Gastrointest Liver Physiol. 2012; 302: G645-G654Crossref PubMed Scopus (62) Google Scholar, 7Fogg M.I. et al.J Allergy Clin Immunol. 2003; 112: 796-797Abstract Full Text Full Text PDF PubMed Scopus (266) Google Scholar This study, however, challenges this as the sole mechanism of esophageal activation by demonstrating direct evidence of the presence of dust mite antigen in esophageal mucosa of patients with active EoE. Further evidence that aeroallergens may act through mechanisms similar to food is the demonstration of antigenic epitopes common to both environmental allergies and food with a 69% shared IgE cross-reactivity in patients with EoE.8Simon D. et al.Allergy. 2013; 68: 945-948Crossref PubMed Scopus (50) Google Scholar Further study is needed to demonstrate the mechanism by which EoE pathways are driven from the presence of epithelial dust mite and likely plant antigens and whether positive staining corresponds to causality or could be an epiphenomenon of incidental antigen passage through dilated intercellular spaces. Author contributions: Method design: Anupama Ravi, Eric V. Marietta, Joseph A. Murray, David A. Katzka. Data collection and experimentation: Debra M. Geno, Anupama Ravi, Eric V. Marietta. Data analysis: David A. Katzka, Anupama Ravi. Writing of the manuscript: Anupama Ravi, Eric V. Marietta, Joseph A. Murray, and Jeffrey A. Alexander. Local Antigen Deposition in Eosinophilic Esophagitis: Implications for Immune ActivationGastroenterologyVol. 157Issue 1PreviewThe mechanisms of immune activation in eosinophilic esophagitis (EoE) continue to be delineated and triggering antigens can be challenging to pinpoint. Whether antigen drives esophageal eosinophil accumulation from the outside in via the lumen, from the inside out via systemic immune signals, or both, remains enigmatic. In this issue of Gastroenterology, a study led by David Katzka and colleagues1 at the Mayo Clinic reports the penetration of dust mite antigen into the esophageal epithelium of adults with EoE. Full-Text PDF