Pathophysiology of Eosinophilic Esophagitis

Abstract

Eosinophilic esophagitis is an emerging disease that is distinguished from gastroesophageal reflux disease by the expression of a unique esophageal transcriptome and the interplay of early life environmental factors with distinct genetic susceptibility elements at 5q22 (TSLP) and 2p23 (CAPN14). Rare genetic syndromes have uncovered the contribution of barrier disruption, mediated in part by defective desmosomes and dysregulated transforming growth factor beta production and signaling, to eosinophilic esophagitis pathophysiology. Experimental modeling has defined a cooperative role of activated eosinophils, mast cells, and the cytokines IL-5 and IL-13, mediated by allergic sensitization to multiple foods. Understanding these processes is opening the way to better treatment based on disrupting allergic inflammatory and type 2 cytokine-mediated responses, including anti-cytokine therapeutics and dietary therapy.

Understanding fibrosis in eosinophilic esophagitis: Are we there yet?

“…Twin studies suggest that common environmental factors such as preterm labor, maternal fever, caesarian delivery, or infant antibiotic or acid suppression use, may increase the risk of EoE . Additionally, the expression of several candidate genes ( TSLP , CAPN14 , EMSY , LRRC32 , STAT6 , and ANKRD27 ) together with allergic triggers, is associated with the development of EoE in susceptible individuals . Gene–environment interactions can be advantageous to reduce the risk of disease if understood, as seen in the reduced risk of EoE development in breastfed patients with a mutation in CAPN14 .…”

“…The optimal timing of therapy is not established, but given its progressive fibrostenotic nature and recurrent relapse off therapy, it seems these patients may require treatment for the duration of their lives. The development of novel therapeutics that target both eosinophil migration (CRTH2 antagonist) and the inflammatory pathway (anti‐IL4RA, anti‐IL‐13, anti‐IL‐5RA) in EoE is ongoing as the understanding of EoE pathophysiology advances. While there are no Food and Drug Administration‐approved treatments for EoE to date in the United States, Jorveza, an orodispersible topical budesonide was recently (November 9, 2017) approved by The European Medicines Agency Committee for Medicinal Products for Human Use for EoE treatment.…”

“…While histologic measure of disease activity focuses on eosinophil density, there may be a cooperative role between eosinophils and mast cells in the pathogenesis of EoE wherein both cells increase TGFB1 expression . TGF‐β1 signaling via the phospho‐SMAD2/3 pathway, may be a central molecular mediator of EoE, as it has been implicated in the five main areas–smooth muscle dysfunction, epithelial remodeling, barrier dysfunction, collagen deposition, and angiogenesis–of disease pathogenesis (Fig.…”

“…Dilated intercellular spaces is a hallmark of a dysregulated epithelial barrier and reflects increased paracellular permeability . Secreted interleukin (IL)‐13 during esophageal inflammation triggers expression of CAPN14 that can lead to a reduction in desmoglein‐1 thereby leading to a loss of barrier integrity . Furthermore, TGF‐β contributes to epithelial barrier dysfunction by reducing the epithelial tight junction protein, claudin 7 .…”

Biomarkers and therapeutic targets: microRNA roles in the pathophysiology, diagnosis and management of eosinophilic esophagitis

“…These immune cells are capable of producing Th2 cytokines and eotaxin family chemokines that sustain chronic inflammation [ Figure 1] [15] . Ultimately, inflammation leads to narrowing of the esophageal lumen and symptoms of solidfood and liquid dysphagia, chest pain, food impaction, acid-reflux and even feeding disorders in children [14,16] .…”