Biology and Treatment of Eosinophilic Esophagitis Marc E. Rothenberg  Gastroenterology  Volume 137, Issue 4, Pages 1238-1249 (October 2009) DOI: 10.1053/j.gastro.2009.07.007 Copyright © 2009 AGA Institute Terms and Conditions

Figure 1 Pathogenesis and treatment of EE. Aeroallergens, food allergens, and skin sensitization have been implicated in the pathogenesis of EE. Therapies such as an elemental diet, systemic glucocorticoids, and anti–IL-5 improve the microscopic features of EE, acting at different steps of pathogenesis. Determining the response to proton pump inhibitors (PPIs), which reduce gastric acidity, is important in the diagnosis of EE; inflammation is still present in patients following administration of these drugs. Allergens induce Th2 cells to produce IL-13, which can cause hyperplasic epithelial cells of the esophagus to overexpress eotaxin-3 and fibroblasts to overexpress periostin and down-regulate filaggrin. Eotaxin-3 and periostin overexpression cooperatively chemoattract CCR3+ cells (Th2 cells). Activated Th2 cells also produce IL-5, which regulates eosinophil numbers and their response to eotaxin-3. Inheritance studies indicate that there is a genetic component to EE; an SNP in eotaxin-3 has been associated with the disease. In addition to eosinophils, mast cells and lymphocytes (including B cells) accumulate in the esophagus to contribute to the local inflammatory responses observed in patients with EE. Gastroenterology 2009 137, 1238-1249DOI: (10.1053/j.gastro.2009.07.007) Copyright © 2009 AGA Institute Terms and Conditions

Figure 2 Effects of eosinophils. Eosinophils are bilobed granulocytes with secondary granules that are stained by eosin; these granules contain 4 primary cationic proteins: EPO, MBP, ECP, and EDN. EDN is a ligand for TLR-2 that induces the Th2 polarizing activity of dendritic cells. EPO, MBP, ECP, and EDN are cytotoxic molecules; ECP and EDN are ribonucleases. Eosinophils respond to diverse stimuli, including nonspecific tissue injury, infections, allergens, and tumors. In addition to releasing the preformed cationic proteins, eosinophils also produce a variety of cytokines, chemokines, lipid mediators, and neuromodulators. Eosinophils communicate directly with T cells and mast cells in a bidirectional manner. Eosinophils can release mitochondrial DNA, which functions as an extracellular trap for bacteria. Eosinophil-derived TGF-β induces fibrosis. Gastroenterology 2009 137, 1238-1249DOI: (10.1053/j.gastro.2009.07.007) Copyright © 2009 AGA Institute Terms and Conditions

Figure 3 Regulation of the Th2 inflammatory response in EE. Food antigens induce Th2 cells to release IL-5 and IL-13, which activate eosinophils and esophageal epithelial cells, respectively. IL-13 induces epithelial cells to produce eotaxin-3 (an eosinophil chemoattractant and activating factor) and down-regulate filaggrin expression. IL-5 and eotaxin-3 activate eosinophils to release MBP and EDN, which activate mast cells and dendritic cells, respectively; mast cell activation contributes to fibrosis. Eosinophils also produce TGF-β, which activates epithelial cells and contributes to hyperplasia, fibrosis, and dysmotility. Reduced production of filaggrin might inhibit esophageal barrier function and perpetuates these processes by promoting local food antigen uptake. Genetic variations that affect expression of these regulatory molecules could contribute to the risk of EE. Gastroenterology 2009 137, 1238-1249DOI: (10.1053/j.gastro.2009.07.007) Copyright © 2009 AGA Institute Terms and Conditions

Figure 4 Diagnosis of EE. Endoscopy is used to obtain biopsy samples from patients with proton pump inhibitor (PPI)-refractory upper gastrointestinal symptoms. These tissue samples are analyzed by microscopy; a minimum of 15 eosinophils/hpf indicates that a patient has EE. Analysis of transcription profiles has indicated dysregulated expression of 1% of the human genome, including overexpression of eotaxin-3, in samples from patients with EE. This gene expression profile can be used to distinguish between biopsy specimens from patients with EE, patients with reflux esophagitis (RE), and normal individuals (NL). In patients successfully treated (Rx) with dietary modification and/or glucocorticoids, eosinophil numbers in biopsy samples are reduced to <1/hpf and the transcriptome more closely resembles that of NL, although there are residual gene expression (*) differences between patients treated for EE and RE and NL. Gastroenterology 2009 137, 1238-1249DOI: (10.1053/j.gastro.2009.07.007) Copyright © 2009 AGA Institute Terms and Conditions