Eosinophilic esophagitis pathophysiology

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1];Associate Editor(s)-in-Chief: Ajay Gade MD[2]]

Overview

Eosinophilic esophagitis is an immunoallergic disorder resulting from the interaction between genetics and environmental triggers such as repeated exposure to food and aeroallergens. Patients presenting with EoE have a history of elevated serum IgE levels, response to interventions such as diet restriction, history of food hypersensitivity. Eosinophils originate from CD34+ myeloid precursor cells in the bone marrow, mature to a granulated state and migrate to vascular spaces. The eosinophils are absent in an otherwise normal esophagus, the presence of the eosinophils in the esophagus suggests GERD or EoE. They tend to be present in all layers of the esophagus in EoE, but predominate in the lamina propria and submucosal regions. The documented cytokine expression profile in the esophageal tissue of EoE patients is that of a TH2 inflammatory response. IL-5 and IL-13 are produced by the type-2 helper T cells (Th2) in response to the antigenic proteins from the food or inhalation. IL-13 further stimulates the epithelial cells of the esophagus to produce large proteins to induce a gene called eotaxin-3, which in turn recruits eosinophils from the peripheral blood into the tissue. IL-5 prolongs the survival of the eosinophils. The activated TH2 response leads to the recruitment and activation of Mast cells degranulate and cause tissue damage and repair. Cytokines produced by TH-1 cells are tumor necrosis factor (TNF)-α, Interferon (IFN)-γ, TNF-α is expressed by the epithelial cells of the esophagus whereas the INF-γ is upregulated by the peripheral T cells. Delayed or type- IV hypersensitivity is the mechanism is involved in the EoE rather than the non-IgE. 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. CD34+ myeloid precursor cells in the bone marrow produce eosinophils and then the eosinophils develop granulation and migrate to vascular spaces. Eosinophils although present in all the layers of the esophagus in patients with EoE, they are predominant in the lamina propria and submucosa of the esophagus. The preformed granule proteins of the eosinophils are ECP- Eosinophil Cationic Protein, MBP- Major Basic Protein, EPO- Eosinophil Peroxidase, EDN- Eosinophil Derived Neurotoxin. Upon the stimulation and the degranulation, the eosinophils release the granule proteins into the tissues. Eosinophils synthesize and release cytokines such as IL-5, IL-13, Transforming growth factor (TGF)-α and -β, Chemokines (eotaxins and RANTES), Lipid mediators such as platelet activating factor (PAF) and leukotriene C4. IL-5, IL-13, and granulocyte-macrophage colony stimulating factor (GM-CSF) can cause the maturation and migration of the eosinophils. Eosinophils cause inflammation in the EoE patients by the following mechanisms Angiogenic molecules from the eosinophils recruits the inflammatory cells and the increase the vascularity. Fibrogenic mediators such as TGF-β1 and matrix metalloproteinase 9 (MMP)-9 causes the airway remodeling. MBP and MMP-9 disrupt the integrity of the epithelial cells of the esophageal through their involvement in smooth muscles, fibroblasts, and cell-adhesion molecules. The above-mentioned processes lead to tissue remodeling eventually causing an overall esophageal dysfunction. 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. 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.

Pathophysiology

• The pathophysiology of the EoE is as follows:
• Eosinophilic esophagitis is an immunoallergic disorder resulting from the interaction between genetics and environmental triggers such as repeated exposure to food and aeroallergens.

• Patients presenting with EoE have a history of:
  • Elevated serum IgE levels
  • Response to interventions such as diet restriction
  • History of food hypersensitivity

• Eosinophils originate from CD34+ myeloid precursor cells in the bone marrow, mature to a granulated state and migrate to the vascular spaces.
• The eosinophils are absent in an otherwise normal esophagus, the presence of the eosinophils in the esophagus suggests GERD or EoE.
• They tend to be present in all layers of the esophagus in EoE, but predominate in the lamina propria and submucosal regions.
• The documented cytokine expression profile in the esophageal tissue of patients is that of a TH2 inflammatory response.
• IL-5 and IL-13 are produced by the type-2 helper T cells (Th2) in response to the antigenic proteins from the food or inhalation.
• IL-13 further stimulates the epithelial cells of the esophagus to produce large proteins to induce a gene called eotaxin-3, which in turn recruits eosinophils from the peripheral blood into the tissue.
• IL-5 prolongs the survival of the eosinophils.
• The activated TH2 response leads to the recruitment and activation of
  • Eosinophils
  • Mast cells
• Mast cells degranulate and cause tissue damage and repair.
• Cytokines produced by TH-1 cells are
  • Tumor necrosis factor (TNF)-α
  • Interferon (IFN)-γ
• TNF-α is expressed by the epithelial cells of the esophagus whereas INF-γ is upregulated by the peripheral T cells.
• Delayed or type- IV hypersensitivity is the mechanism is involved in the 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.
• The preformed granule proteins of the eosinophils are
  • ECP- Eosinophil Cationic Protein
  • MBP- Major Basic Protein
  • EPO- Eosinophil Peroxidase
  • EDN- Eosinophil Derived Neurotoxin
• Upon the stimulation and the degranulation, the eosinophils release the granule proteins into the tissues.
• Eosinophils synthesize and release cytokines such as
  • IL-5
  • IL-13
  • Transforming growth factor (TGF)-α and -β
  • Chemokines (eotaxins and RANTES)
  • Lipid mediators such as platelet activating factor (PAF) and leukotriene C4
• IL-5, IL-13, and granulocyte-macrophage colony stimulating factor (GM-CSF) can cause the maturation and migration of the eosinophils.

• Eosinophils cause inflammation in the EoE patients by the following mechanisms
  • Angiogenic molecules from the eosinophils recruits the inflammatory cells and increase the vascularity.
  • Fibrogenic mediators such as TGF-β1 and matrix metalloproteinase 9 (MMP)-9 causes the airway remodeling.
  • MBP and MMP-9 disrupt the integrity of the epithelial cells of the esophagus through their involvement in the smooth muscles, fibroblasts, and cell-adhesion molecules.
  • The above-mentioned processes lead to tissue remodeling eventually, causing an overall esophageal dysfunction.
  • 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.
  • These findings not only highlight the importance of targeting fibrosis reversal in the treatment of EoE, but also underline the importance of eosinophils in tissue remodeling.

Gross Pathology

• Mucosal biopsies of the esophagus should be obtained in all patients in whom EoE is a clinical possibility regardless of the endoscopic appearance.
• Endoscopic abnormalities in patients with EoE are as follows:
  • Fixed esophageal ring which is corrugated
  • White exudate
  • Longitudinal furrows
  • Mucosal pallor
  • Diffuse esophageal narrowing
  • Mucosal fragility leading to esophageal lacerations during the endoscopy
• However, because these endoscopic features have been described in other esophageal disorders, none can be considered pathognomonic for EoE.

• 

  Endoscopy of the esophagus: Eosinophilic esophagitis
  Source: Wikimedia

Histopathology

• Characteristic features are as follows:
  • > 20 eosinophils/0.24 mm2.
  • Papillae are elongated
  • Papillae reach into the top 1/3 of the epithelial layer
  • Basal cell hyperplasia; > 3 cells thick or >15% of epithelial thickness

H&E stain of esophagus biopsy showing eosinophilic esophagitis, manifested by an infiltration of eosinophils in the lamina propria

References

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