Sandbox:ajay

• Genetic predisposition may deem an individual vulnerable to the environmental triggers resulting in EoE.
• Frequently, patients presenting with EoE have a history of food or aeroallergen hypersensitivity, elevated serum IgE, and responsiveness to diet restriction or anti-allergy therapy.
• Food hypersensitivity has been reported in 19–73% of children and 13–25% of adults with EoE.
• The reason for lower rates of food hypersensitivity in adults is unclear, but this feature may mean that adults are less responsive to diet restriction.
• Regardless, EoE is considered an immunoallergenic disorder, whereby esophageal inflammation results from repeated exposure to food and aeroallergens in genetically susceptible individuals.
• The documented cytokine expression profile in the esophageal tissue of EoE patients is that of a TH2 inflammatory response.
• The activated TH2 response leads to the recruitment and activation of eosinophils and mast cells, which degranulate, releasing products that instigate tissue damage and repair.
• Interestingly, TH1 cytokines including tumor necrosis factor (TNF)-α (expressed by esophageal epithelial cells) and interferon (IFN)-γ (up-regulated by peripheral blood T cells) (40) are also found in increased numbers in esophageal biopsies.
• This may explain the non-IgE, type IV hypersensitivity (cell-mediated) mechanism of EoE.
• It is postulated that the EoE-defining endoscopic and histologic manifestations are a culmination of the disease process which, may have debilitating long-term effects including strictures and food impactions in untreated or poorly managed cases of EoE.
• Eosinophils originate from CD34+ myeloid precursor cells in the bone marrow, mature to a granulated state and migrate to vascular spaces.
• They tend to be present in all layers of the esophagus in EoE, but predominate in the lamina propria and submucosal regions.
• Eosinophils contain many preformed granule proteins including eosinophil cationic protein (ECP), major basic protein (MBP) eosinophil peroxidase (EPO), and eosinophil-derived neurotoxin (EDN), which are released into tissues upon stimulation and degranulation.
• Additionally, eosinophils synthesize and release cytokines including IL-5, IL-13, transforming growth factor (TGF)-α and -β, chemokines (eotaxins and RANTES), and lipid mediators such as platelet activating factor (PAF) and leukotriene C4.
• The process of eosinophil maturation and migration is stimulated by IL-5, IL-13, and granulocyte-macrophage colony stimulating factor (GM-CSF).
• Eosinophil-derived angiogenic molecules may increase vascularity and facilitate inflammatory cell recruitment.
• TGF-β1 and matrix metalloproteinase 9 (MMP)-9 are fibrogenic mediators implicated in airway remodeling.
• Additionally, MBP and MMP-9 have been implicated in the disruption of esophageal epithelial integrity through their involvement in smooth muscles, fibroblasts, and cell-adhesion molecules.
• These processes may culminate in overall esophageal dysfunction through the consequent tissue remodeling.
• Eosinophils are considered the main effector cells in fibrosis in a variety of hypereosinophilic syndromes and eosinophil-related allergic diseases including asthma and EoE.
• TGF-β and eosinophilic granule proteins MBP and EPO are the key eosinophil effector proteins. The importance of eosinophils in mediating tissue fibrosis is supported by evidence in both murine and human models.
• Interestingly, a recent study on fibrosis reversal with dietary and steroid therapy showed that improvement in esophageal eosinophilia and eosinophil degranulation within the epithelium was strongly associated with fibrosis reversal and symptom improvement.
• This finding is consistent with Kagalwalla et al., who found improvements in epithelial remodeling in both dietary and corticosteroid therapy, and also found these improvements to be directly associated with improvement in esophageal eosinophilia.
• These findings not only highlight the importance of targeting fibrosis reversal in treatment of EoE, but also underline the importance of eosinophils in tissue remodeling.

Pathogenesis

• The eosinophils are absent in an otherwise normal esophagus, the presence of the eosinophils in the esophagus suggests GERD or EoE.