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Chatty neighboring cells promote eosinophilic esophagitis

Messages exchanged among a network of “talkative” immune and esophageal cells may be important in determining whether people with eosinophilic esophagitis (EoE) go on to develop a more severe form of the disease. EoE is a chronic disease, often associated with food allergies and marked by immune cell infiltration and impaired functioning of the esophagus, including difficulty swallowing food and drink. In some people, but not others, the disease progresses to tissue damage, inflammation and esophageal narrowing, and ulcers, at which point treatment is less effective. It is important to understand what causes the disease to progress—and why it only progresses in some people—so researchers could develop new ways to stop it before it becomes harder to treat.

To this end, the Consortium of Eosinophilic Gastrointestinal Disease Researchers, funded in part by NIDDK, set out to uncover the exact mechanisms at work behind progression of EoE. To do this, they analyzed esophageal biopsies from children and adults with EoE at 11 study sites. They compared biopsies from those whose disease had progressed to esophageal damage and narrowing with another group whose disease had not progressed. Progressive EoE was more common in adults, women, and in people with a longer duration of EoE. An analysis of possible genetic factors associated with disease progression, using a diagnostic panel of 94 gene products typically linked to EoE, showed that biopsies from those with progressive EoE showed lower activity in a gene called TSPAN12, specifically within endothelial cells (cells that line blood vessels) in the esophagus. To explore how this reduced TSPAN12 activity could play a role in EoE progression, the investigators pivoted to a cell model grown in a culture dish. They found an elaborate “social” cell network in which an inflammatory chemical called IL-13 from immune cells caused nearby endothelial cells to lose their TSPAN12 activity, which then signaled to neighboring fibroblasts (cells that form connective tissue) to lay down more scar tissue, similar to progressive EoE. Returning to the clinical context, the researchers observed that treatment with an antibody that blocks IL-13 in people with EoE restored esophageal TSPAN12 activity.

This study uncovers some of the unique disease processes at work in the progressive form of EoE. Knowledge of these pathways can help point to more personalized approaches to therapy and prevention of disease progression.

Shoda T, Wen T, Caldwell JM, …Rothenberg ME; Consortium of Eosinophilic Gastrointestinal Disease Researchers (CEGIR) Investigators Group. Loss of endothelial TSPAN12 promotes fibrostenotic eosinophilic esophagitis via endothelial cell-fibroblast crosstalk. Gastroenterology 162: 439-453, 2022.

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