Evaluation of the vascular barrier in eosinophilic esophagitis

Thesis Summary Background and Aims Eosinophilic esophagitis (EoE) is a chronic, immune-mediated condition where type 2 inflammation has a prominent role and is associated with significant atopic multimorbidity and a relevant disease burden. The pathogenesis of EoE is still elusive. More precisely, The esophageal barrier has been investigated until now on the epithelial side only. Mucosal vascular barrier dysfunction has been recently implicated in several immune-mediated gastrointestinal disorders. We have here characterized the esophageal vascular barrier (EVB) in EoE by assessing the vascular barrier marker plasmalemma vesicle-1 (PV-1). Methods Probe-based confocal laser endomicroscopy (pCLE) was performed in two EoE and two reflux esophagitis patients. One EoE patients was also evaluated after treatment with dupilumab, a monoclonal antibody targeting interleukin (IL)-4 and IL-13. PV-1 was investigated by both immunohistochemistry and qPCR in esophageal biopsies of 16 patients with EoE, 15 with reflux esophagitis, and 15 healthy controls. Results In EoE, but not in reflux esophagitis, pCLE revealed leakage of the EVB, which was restored after dupilumab in the treated patient. PV-1 was significantly increased in EoE in comparison to RE and healthy controls (p<0.01 for both comparisons), both in terms of protein and transcript levels. Moreover, PV-1 levels, as assessed by immunohistochemistry and qPCR, correlated with eosinophil infiltrating numbers (r =0.66 and 0.79, respectively, both p<0.01). Conclusions EVB appears to be disrupted in active EoE. This finding might have both diagnostic and therapeutical implications. More precisely, on the diagnostic and monitoring side, vascular leakiness assessed by pCLE could be a marker of EoE especially in those cases devoid of overt endoscopic findings, might anticipate the histological diagnosis and facilitate the collection of targeted biopsies, and could help in monitoring the mucosal recovery after therapy. Moreover, the altered permeability of the EVB could provide a pathophysiological explanation of the abnormal translocation of allergens together with eosinophils from other inflammation sites, such as the respiratory tract to the esophageal mucosa, a possible mechanism triggering an exaggerated Th2 response in the esophageal mucosa of EoE patients.