Epithelial origin of eosinophilic esophagitis

Abstract

Eosinophilic esophagitis (EoE) is a chronic, allergen-driven inflammatory disease of the esophagus characterized predominantly by eosinophilic inflammation, leading to esophageal dysfunction. Converging data have placed the esophageal epithelium at the center of disease pathogenesis. In particular, the main EoE disease susceptibility loci at 2p23 and 5p22 encode for gene products that are produced by the esophageal epithelium: the intracellular protease calpain 14 and thymic stromal lymphopoietin, respectively. Furthermore, genetic and functional data establish a primary role for impaired epithelial barrier function in disease susceptibility and pathoetiology. Additionally, the EoE transcriptome, a set of genes dysregulated in the esophagi of patients with EoE, is enriched in genes that encode for proteins involved in esophageal epithelial cell differentiation. This transcriptome has a high proportion of esophagus-specific epithelial genes that are notable for the unexpected enrichment in genes encoding for proteases and protease inhibitors, as well as in IL-1 family genes, demonstrating a previously unappreciated role for innate immunity responses in the esophagus under homeostatic conditions. Among these pathways, basal production of the serine protease inhibitor, Kazal-type 7 (SPINK7) has been demonstrated to be part of the normal differentiation program of esophageal epithelium. Profound lost expression of SPINK7 occurs in patients with EoE and is sufficient for unleashing increased proteolytic activity (including urokinase plasminogen activator), impaired barrier function, and production of large quantities of proinflammatory and proallergic cytokines, including thymic stromal lymphopoietin. Collectively, we put forth a model in which the esophagus is normally equipped as an anti-inflammatory sensing organ and that defects in this pathway, mediated by epithelial protease/protease inhibitor imbalances, unleash inflammatory responses resulting in disorders, such as EoE.

Epithelial barrier repair and prevention of allergy

“…Eosinophilic esophagitis (EoE) is considered a type 2 immune disease and often coexists with AD, asthma, and FA (13). The mucosa of the human esophagus is lined by the multilayer squamous nonkeratinized epithelium, which provides a protective barrier against environmental insults.…”

“…These diseases have in common a dysfunctional epithelial barrier, resulting in the penetration of allergens and microbes, accompanied by the release of epithelial-derived cytokines (e.g., thymic stromal lymphopoietin [TSLP], IL-25, IL-33), which drive type 2 immune responses. Although other immune pathways can modify the course of illness, cytokines including IL-4, IL-13, IL-31, TSLP, and IL-33 play a key role in allergic diseases (4-8), eliciting local tissue injury and repair (5,(9)(10)(11)(12)(13)(14).AD is the most prevalent chronic inflammatory skin disease (3,(15)(16)(17)(18)(19). In a subset of allergic patients, it is thought that ADrelated skin epithelial dysfunction contributes to the atopic march, which starts with AD and often leads directly to FA (20-23).…”

“…These diseases have in common a dysfunctional epithelial barrier, resulting in the penetration of allergens and microbes, accompanied by the release of epithelial-derived cytokines (e.g., thymic stromal lymphopoietin [TSLP], IL-25, IL-33), which drive type 2 immune responses. Although other immune pathways can modify the course of illness, cytokines including IL-4, IL-13, IL-31, TSLP, and IL-33 play a key role in allergic diseases (4)(5)(6)(7)(8), eliciting local tissue injury and repair (5,(9)(10)(11)(12)(13)(14).…”

Toll‐like receptor 2 stimulation augments esophageal barrier integrity

“…The pathophysiology of EoE is thought to arise from the presence of food allergens in contact with the esophageal mucosa, which causes a T-helper type 2 (Th2) immune response leading to mucosal inflammation and eosinophilia, epithelial dysfunction, and long-term fibrosis. 1 Epithelial barrier dysfunction plays a critical role in this process because it promotes continued exposure to allergens and microbiota in the esophageal lumen, which stimulates epithelial cells and leukocytes to release chemokines and cytokines. 2,3 Decreased barrier integrity in EoE has been measured by loss of mucosal impedance in vivo and transepithelial electrical resistance in vitro.…”

Esophageal IgE, IgG4, and mucosal eosinophilia in individuals with dysphagia

“…Because of its association with Castleman disease, eosinophilic granulomatosis with polyangiitis, and sarcoidosis, elevated IgG4 is thought to represent a marker of mucosal barrier breakdown, rather than a direct trigger. Genomewide association studies have identified several genes associated with epithelial barrier abnormalities through genetic and epigenetic mechanisms . Tissue eosinophilia has also been reported in other diseases, such as chronic rhinosinusitis with nasal polyps and nonallergic rhinitis with eosinophilia syndrome, where nonspecific inflammation has been suggested to result from antigen exposure in the setting of a primary epithelial barrier abnormality …”