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Mechanisms of gastrointestinal allergic disorders
Nurit P. Azouz, Marc E. Rothenberg
Nurit P. Azouz, Marc E. Rothenberg
Published March 11, 2019
Citation Information: J Clin Invest. 2019;129(4):1419-1430. https://doi.org/10.1172/JCI124604.
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Review Series

Mechanisms of gastrointestinal allergic disorders

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Abstract

Gastrointestinal (GI) allergic disease is an umbrella term used to describe a variety of adverse, food antigen–driven, immune-mediated diseases. Although these diseases vary mechanistically, common elements include a breakdown of immunologic tolerance, a biased type 2 immune response, and an impaired mucosal barrier. These pathways are influenced by diverse factors such as diet, infections, exposure to antibiotics and chemicals, GI microbiome composition, and genetic and epigenetic elements. Early childhood has emerged as a critical period when these factors have a dramatic impact on shaping the immune system and therefore triggering or protecting against the onset of GI allergic diseases. In this Review, we will discuss the latest findings on the molecular and cellular mechanisms that govern GI allergic diseases and how these findings have set the stage for emerging preventative and treatment strategies.

Authors

Nurit P. Azouz, Marc E. Rothenberg

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Figure 1

The regulation of epithelial barrier function in EoE.

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The regulation of epithelial barrier function in EoE.
Esophageal allergi...
Esophageal allergic responses to food antigens are driven by barrier impairment. Decreases in the esophageal levels of the serine protease SPINK7 lead to increased serine protease activity, which impairs epithelial barrier function and in turn causes innate epithelial proinflammatory responses, including TSLP production. TSLP promotes Th2 responses. This reaction can be controlled by anti-TSLP, anti–IL-13, and/or anti–IL-4R antibodies. In addition, loss of SPINK7 promotes increased esophageal uPA activity that activates eosinophils. Antiprotease replacement of SPINK7, such as A1AT delivery, could potentially restore these pathways. Increased IL-13 promotes epithelial cells to produce eotaxin-3 that attracts eosinophils to the esophagus. Anti–IL-5, anti–IL-5R, and anti–Siglec-8 therapy reduce and/or eliminate eosinophils. IL-13 also induces decreased expression of the desmosomal protein DSG1, thereby impairing the epithelial barrier, as well as increased expression of the cysteine protease CAPN14, which also impairs the epithelial barrier. Therapeutic reagents that are FDA approved or in clinical trials are shown in red and blue, respectively.
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