Mucosal Penetration and Clearance of Gluten and Milk Antigens in Eosinophilic Oesophagitis

Anupama Ravi; Eric V. Marietta; Jeffrey A. Alexander; Kathryn Peterson; Crystal Lavey; Debra M. Geno; Joseph A. Murray; David A. Katzka


Aliment Pharmacol Ther. 2021;53(3):410-417. 

In This Article

Abstract and Introduction


Background: The Th2 allergic pathway in eosinophilic oesophagitis (EoE) responds to food antigen exposure.

Aim: To compare the presence and temporal pattern of food antigen penetration in oesophageal mucosa in active and inactive EoE and controls

Methods: Thirty-two patients with EoE (20 active) and 10 controls were asked to eliminate all wheat and/or dairy 12, 24, 48, 72 or 96 hours before endoscopy. Immunostaining on endoscopic biopsies was performed for gliadin, casein and whey.

Results: Gluten, casein and whey were detected by positive staining in 17/32 (53.1%), 21/32 (65.6%), and 30/32 (92.0%) of patients, respectively. In active vs inactive EoE, 70.0% vs 25.0% (P < 0.05), 80.0% vs 41.5%, and 90.0% vs 90.9% patients had detectable gliadin, casein and whey, respectively. Casein and whey (20.0% and 100%, respectively) but not gliadin, were present in controls. The gliadin staining density was greater in active compared to inactive disease at ≤ 24 vs >24 hours after exposure (P = 0.05) but no differences were detected when comparing active and inactive patients for casein and whey. There was greater staining density for whey than casein for all patients at ≤24 hours (mean 2.14 ± 0.91 and 1.07 ± 1.33, P = 0.02). In active EoE, IgG4 was present in 14/20 compared to one inactive patient.

Conclusion: The oesophageal epithelium is selectively permeable and has relatively long dwell times for food antigens known to trigger EoE. The precise mechanism of antigen-specific mucosal entry and the factors that determine the induction or effector trigger of the Th2 pathway activation merit further study.


Eosinophilic oesophagitis (EoE) is a chronic disease in which epithelial exposure to food antigen activates a cascade of diffuse inflammatory events commonly leading to remodelling of the oesophageal wall with stricture formation.[1] This inflammatory pathway has been carefully dissected through elegant research revealing a coordinated cascade of inflammatory cytokines such as IL-4, 5, and 13, immunoglobulins such as IgG4 and the cellular infiltration of eosinophils, mast cells and lymphocytes.[2] One facet of EoE pathogenesis that is less well defined is the process of antigen presentation and recognition initiating the local inflammatory cascade although several aspects have been described. This includes the role of oesophageal epithelial cells as potential nonprofessional antigen presenting cells[3] and recognition and activation of T lymphocytes by eosinophils after antigen exposure.[4] Another study has demonstrated elevation of key cell surface proteins associated with antigen presentation, such as HLA-DR, CD3, CD28, CD40 and CD138, significantly increased with food reintroduction.[5]

It has been assumed that this recognition occurs on the surface of or within the oesophageal epithelium but less data are available to prove this. Studies from our group have demonstrated that ingested gluten antigen is present in the epithelium of patients with EoE and is dependent on disease activity, more specifically through increased mucosal permeability.[6] This antigen prevalence study opens the field for numerous additional questions including the time line of antigen persistence in the mucosa and whether the pattern of food protein penetration is similar across a range of antigens. More specifically, it is unknown what the dwell time for food antigens is once entering the oesophageal mucosa in patients with EoE. Furthermore, we have only studied one food antigen to date and it is not known if all food antigens similarly enter the oesophageal mucosa, are dependent on EoE activity and remain in the mucosa for similar durations of time. The answers to these questions could be important to understanding how the oesophagus allows protein entry and exit. Furthermore, these results could drive clinical recommendations on the duration of food avoidance required to treat EoE and the oesophageal tolerance for key food antigens based on their degree of mucosal penetration. It is hypothesised that food antigens will have differential ability to penetrate and remain in the oesophageal mucosa based on EoE activity and specific properties of the antigen. The aim of this study was to assess the relationship between timed avoidance and presence of wheat and dairy antigens in patients with active EoE, resolved EoE and controls.