Eotaxin-3 and a uniquely conserved gene-expression profile in eosinophilic esophagitis
Carine Blanchard, … , Bruce J. Aronow, Marc E. Rothenberg
Carine Blanchard, … , Bruce J. Aronow, Marc E. Rothenberg
Published February 1, 2006
Citation Information: J Clin Invest. 2006;116(2):536-547. https://doi.org/10.1172/JCI26679.
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Eotaxin-3 and a uniquely conserved gene-expression profile in eosinophilic esophagitis

Abstract

Eosinophilic esophagitis (EE) is an emerging disorder with a poorly understood pathogenesis. In order to define disease mechanisms, we took an empirical approach analyzing esophageal tissue by a genome-wide microarray expression analysis. EE patients had a striking transcript signature involving 1% of the human genome that was remarkably conserved across sex, age, and allergic status and was distinct from that associated with non-EE chronic esophagitis. Notably, the gene encoding the eosinophil-specific chemoattractant eotaxin-3 (also known as CCL26) was the most highly induced gene in EE patients compared with its expression level in healthy individuals. Esophageal eotaxin-3 mRNA and protein levels strongly correlated with tissue eosinophilia and mastocytosis. Furthermore, a single-nucleotide polymorphism in the human eotaxin-3 gene was associated with disease susceptibility. Finally, mice deficient in the eotaxin receptor (also known as CCR3) were protected from experimental EE. These results implicate eotaxin-3 as a critical effector molecule for EE and provide insight into disease pathogenesis.

Authors

Carine Blanchard, Ning Wang, Keith F. Stringer, Anil Mishra, Patricia C. Fulkerson, J. Pablo Abonia, Sean C. Jameson, Cassie Kirby, Michael R. Konikoff, Margaret H. Collins, Mitchell B. Cohen, Rachel Akers, Simon P. Hogan, Amal H. Assa’ad, Philip E. Putnam, Bruce J. Aronow, Marc E. Rothenberg

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Figure 10

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Cellular and molecular mediators in EE. Microscopic assessment (lower pa...
Cellular and molecular mediators in EE. Microscopic assessment (lower panel; magnification, ×100) using a tryptase-specific antibody demonstrates scattered mast cells (bright-red-fluorescent cells marked by white arrows) among cytokeratin-positive epithelial cells (green-fluorescent cells, which are appropriately absent from the fibrovascular stroma within a papilla, marked “P”). Two eosinophils are designated by dashed circles. Eosinophils are identified by their characteristic red autofluorescence and nuclear morphology under higher magnification (e.g., lower left cell in top left panel; magnification, ×1000; green channel omitted). Nuclei are fluorescently counterstained (blue) with DAPI. We propose a model of EE pathogenesis involving eotaxin-3 expression by epithelioid cells. Eotaxin-3 overexpression promotes chemoattraction of CCR3-positive eosinophils and expression of the CLC protein. An SNP in the eotaxin-3 gene is associated with EE. Mast cells (white arrows) accumulate in the esophagus, and mast cell genes (tryptase-α and carboxypeptidase A3) are overrepresented in the EE transcript signature (Supplemental Table 5). Eotaxin-3 drives eosinophil activation that leads to tissue damage. CRISP-3, cysteine-rich secretory protein-3.