Esophageal Mucosal Permeability as a Surrogate Measure of Cure in Eosinophilic Esophagitis

Abstract

This study aimed to evaluate the relationship of esophageal epithelial permeability with mast cell infiltration and IgG4 deposits as well as chemokine levels in eosinophilic esophagitis (EoE) patients before and after treatment. Biopsies from controls and EoE patients before and after treatment were analyzed. Hematoxylin and eosin staining was used to show eosinophil infiltration. Paracellular permeability of the esophageal epithelium was assessed using surface biotinylation. Immunohistochemical staining was performed to examine mast cell infiltration and IgG4 deposits. Gene expression of chemokines was evaluated by qRT-PCR. Esophageal epithelial infiltration of mast cells, IgG4 deposits, and permeability were significantly increased in EoE patients. Levels of interleukin-13, calpain-14, and eotaxin-3 mRNAs were significantly upregulated, while filaggrin, serine peptidase inhibitor Kazal type 7 (SPINK7), and involucrin mRNAs were significantly downregulated in EoE patients. In patients achieving histologic remission diagnosed by eosinophil counts, a subset of EoE patients with unchanged permeability after treatment showed increases in mast cell infiltration, IgG4 deposits, and interleukin-13, calpain-14, filaggrin, and SPINK7 expression, with decreased eotaxin-3 and involucrin. Other EoE patients with decreased permeability displayed decreased eotaxin-3, involucrin, and mast cell infiltration, no IgG4 deposits, and increased IL-13, calpain-14, filaggrin, and SPINK7. Increased permeability of the esophagus in EoE patients without eosinophil infiltration after treatment was associated with mast cell infiltration and IgG4 deposits.

Regulatory T cells Are Increased and Correlate With Mast Cells in Eosinophilic Esophagitis

“… 7 , 26 , 27 Levels of FLG mRNA were decreased in EoE patients, consistent with previous studies. 6 , 19 However, even without histologic remission, levels of FLG mRNA were upregulated in EoE patients after treatments, indicating that the genes related to barrier function tend to recover first.…”

“…In the present study, mast cells were increased in esophageal epithelium of EoE patients, consistent to previous studies. 9 , 19 , 28 Mast cells that infiltrate into the esophageal epithelia release mediators involved in the remodeling of those layers. 20 , 29 Previous studies have found that mast cell counts could be used as a marker of EoE activity in addition to eosinophil count.…”

“… 1 , 2 We used a previously described method to process samples. 19 Briefly, controls were patients who underwent endoscopy due to clinical complaints, with 0 eosinophils per high-power field (HPF) and no histologic or endoscopic evidence of EoE. 20 Biopsies of esophagus from controls and patients with EoE before and after treatments were taken.…”

“…One sample was used for measurement of messenger RNA (mRNA) levels, and another one from same region was used for immunohistochemical and hematoxylin and eosin staining. 19 This study was performed with approval from the Ethics Committee of Hyogo Medical University (No. 174).…”

How should we interpret the data of eosinophilic esophagitis patients from an academic institution?

“…Treatment responses have not been clearly defined, and normalizing mucosal eosinophil counts alone is not sufficient to achieve treatment goals 12 . However, the normalization of the esophageal mucosal barrier might signal treatment success and the cure of EoE 13 . Moreover, the rates of recurrence without treatment and the remission of EoE are still unclear.…”