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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Research Article Immunology

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 1

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Microarray analysis of the transcripts expressed in esophageal biopsies....
Microarray analysis of the transcripts expressed in esophageal biopsies. RNA from each patient was subjected to chip analysis using Affymetrix Human Genome U133 Plus 2.0 GeneChips. The normal (NL) group is composed of 6 individuals (numbers 1–6), the CE group is represented by 5 patients (numbers 7–11), and 13 patients (numbers 12–24) are in the EE group, as reported in Supplemental Table 1. (A) The 574 genes differentially expressed (P < 0.01) in the EE group compared with normal healthy patients have been ordered (standard correlation); upregulated genes are represented in red and downregulated genes in blue. The magnitude of the gene changes is proportional to the darkness of the color. Each column represents a separate individual and each line a gene. (B and C) EE transcript signature is presented as a function of the allergic status and sex of EE patients. Average expression of the transcripts of the EE signature is depicted in the non–allergen-sensitized (n = 4) and allergen-sensitized EE patients (n = 9) (B) and in female (n = 5) and male EE patients (n = 8) (C). (D) The 574 genes expressed significantly differently (P < 0.01) in the EE group compared with normal healthy patients and the 228 genes expressed differently (P < 0.01) in the CE group compared with normal healthy patients have been analyzed by cluster analysis and ordered (distance) using GeneSpring software. Clusters 1, 2, and 3 highlight the CE transcripts, and clusters 4 and 5 highlight the EE transcripts. The eosinophil (Eos) count in each patient is shown in the lower panel.