Biology and treatment of eosinophilic esophagitis - PubMed (original) (raw)

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Biology and treatment of eosinophilic esophagitis

Marc E Rothenberg. Gastroenterology. 2009 Oct.

Abstract

Eosinophilic esophagitis is a recently recognized but expanding disorder characterized by antigen-driven eosinophil accumulation in the esophagus. Symptoms frequently mimic those of gastroesophageal reflux disease, but the diseases are distinct in their histopathology, gene expression signature, response to therapy, hereditary risk, and association with allergies. The pathogenesis of eosinophilic esophagitis involves environmental and genetic factors, particularly food antigens and expression level of the eosinophil chemoattractant eotaxin-3, respectively. Analyses of gene expression signatures and animal models have indicated the importance of adaptive T-cell immunity that involves interleukin-5 and interleukin-13-induced esophageal epithelial cell responses. Symptoms, dysregulation of esophageal gene expression, and pathology are largely reversible following reduced exposure to specific food antigens as well as anti-inflammatory therapy, but chronic treatment is necessary to prevent relapse. Therefore, eosinophilic esophagitis is a disease with unique features that include chronic esophagitis, atopy, immune sensitization to oral antigens, reversibility, and familial association.

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Figures

Figure 1

Figure 1. Molecular and cellular mechanisms involved in EE pathogenesis, eotaxin-3-associated eosinophil recruitment and treatments

Aeroallergen, food allergen and skin sensitization have been implicated in EE pathogenesis. Elemental diet, glucocorticoids, and anti-IL-5 treatments improve the microscopic features of EE acting at different levels on the disease pathogenesis. Proton pomp inhibitors (PPI) are important in establishing the diagnosis of EE as inflammation should be present on PPIs therapy. Hyperplasic epithelial cells of the esophagus overexpress eotaxin-3 in response to IL-13. Fibroblasts overexpress periostin and downregulate filaggrin likelyin response to IL-13. Eotaxin-3 and periostin overexpression cooperatively chemoattract CCR3+ cells, a process primed by IL-5 which regulates eosinophil responsiveness to eotaxin-3 and the circulating level of eosinophils. Inheritance of EE disease suggests a genetic predisposition. A SNP in the eotaxin-3 gene has been associated with EE. In addition to eosinophils, mast cells and lymphocytes including B cells accumulate in the esophagus of EE patients and likely contribute to the local inflammatory responses.

Figure 2

Figure 2. Schematic diagram of the multifunctional effects of eosinophils

Eosinophils are bilobed granulocytes with eosinophilic staining secondary granules. The secondary granules contain four primary cationic proteins designated eosinophil peroxidase (EPO), major basic protein (MBP), eosinophil cationic protein (ECP), and eosinophil derived neurotoxin (EDN). EDN is a ligand for Toll like receptor (TLR)2 and induces the Th2 polarizing ability of dendritic cells. All four proteins are cytotoxic molecules; in addition, ECP and EDN are ribonucleases. Eosinophils respond to diverse stimuli including non-specific tissue injury, infections, allergens and tumors. In addition to releasing their preformed cationic proteins, eosinophils also release a variety of cytokines, chemokines, lipid mediators, and neuro-modulators. Eosinophils directly communicate with T cells and mast cells in a bidirectional manner. Eosinophils are capable of catapulting their mitochrondrial DNA which can serve as extracellular traps for bacteria. Eosinophil derived TGF-β induces fibrosis.

Figure 3

Figure 3. Molecular regulation of the Th2 inflammatory response in EE

Food antigen triggered T helper type 2 (Th2) cells release IL-5 and IL-13 which target eosinophils and esophageal epithelial cells, respectively. IL-13 triggered responses include marked production of the eosinophil chemoattactrant and activating factor eotaxin-3 by epithelial cells as well as down regulation of filaggrin expression. Activated eosinophils release MBP and EDN which target mast cells and dendritic cells, respectively. Eosinophil derived TGF-β and MBP target fibroblasts, epithelial cells and smooth muscle cells and contribute to cellular hyperplasia, fibrosis and dysmotility. In addition, mast cell activation contributes to fibrosis. Perhaps reduced esophageal barrier function (mediated by decreased filaggrin) perpetuates the process by promoting local food antigen uptake. Genetic variants in regulatory molecules involved in these steps may contribute to EE disease risk.

Figure 4

Figure 4. Molecular and histological diagnosis of EE

Patients with PPI refractory upper gastrointestinal symptoms undergo endoscopic biopsy. Tissue is analyzed microscopically and a minimal level of 15 peak eosinophils per hpf is required for diagnosis. In addition, molecular profiling reveals dysregulated expression of 1% of the human genome including eotaxin-3 overexpression that readily distinguishes biopsies from EE, reflux esophagitis (RE) and normal individuals (NL). Following treatment (Rx) with dietary modification and/or glucocorticoids, endoscopic analysis reveals complete resolution of esophageal eosinophilia and large normalization of the EE transcriptome. Residual abnormal gene expression (*) differentiates treated EE from NL and esophagitis RE patients.

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References

    1. Mishra A, Hogan SP, Lee JJ, Foster PS, Rothenberg ME. Fundamental signals that regulate eosinophil homing to the gastrointestinal tract. J Clin Invest. 1999;103:1719–1727. - PMC - PubMed
    1. Rothenberg ME. Eosinophilic gastrointestinal disorders (EGID) J Allergy Clin Immunol. 2004;113:11–28. - PubMed
    1. Balatsinou C, Milano A, Caldarella MP, Laterza F, Pierdomenico SD, Cuccurullo F, Neri M. Eosinophilic esophagitis is a component of the anticonvulsant hypersensitivity syndrome: Description of two cases. Dig Liver Dis. 2007 - PubMed
    1. Noble C, Francis L, Withers GW, Ee LC, Lewindon PJ. Audit of eosinophilic oesophagitis in children post-liver transplant. Pediatr Transplant. 2008 - PubMed
    1. Furuta GT, Liacouras CA, Collins MH, Gupta SK, Justinich C, Putnam PE, Bonis P, Hassall E, Straumann A, Rothenberg ME. Eosinophilic esophagitis in children and adults: a systematic review and consensus recommendations for diagnosis and treatment. Gastroenterology. 2007;133:1342–1363. - PubMed

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