Eosinophilic esophagitis: Epithelial mesenchymal transition contributes to esophageal remodeling and reverses with treatment Amir F. Kagalwalla, MD,

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Eosinophilic esophagitis: Epithelial mesenchymal transition contributes to esophageal remodeling and reverses with treatment Amir F. Kagalwalla, MD, Noorain Akhtar, MD, Samantha A. Woodruff, MD, Bryan A. Rea, BA, Joanne C. Masterson, PhD, Vincent Mukkada, MD, Kalyan R. Parashette, MD, Jian Du, MD, Sophie Fillon, PhD, Cheryl A. Protheroe, BA, James J. Lee, PhD, Katie Amsden, BS, Hector Melin-Aldana, MD, Kelley E. Capocelli, MD, Glenn T. Furuta, MD, Steven J. Ackerman, PhD Journal of Allergy and Clinical Immunology Volume 129, Issue 5, Pages 1387-1396.e7 (May 2012) DOI: 10.1016/j.jaci.2012.03.005 Copyright © 2012 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig 1 Six-point EMT assessment scale for quantitation in esophageal biopsy specimens. Representative merged confocal images of immunofluorescent staining for cytokeratin (green) and vimentin (red) with 4′-6-diamidino-2-phenylindole dihydrochloride–stained nuclei (blue) is shown. The EMT score is indicated on the left, with descriptions of the characteristics of EMT biomarker staining relative to changes in epithelial architecture on the right. The score incorporates (1) the location and amount of vimentin-positive (mesenchymal marker) cell staining within the epithelium and (2) decreased cytokeratin (epithelial marker) staining in hyperplastic epithelium. Journal of Allergy and Clinical Immunology 2012 129, 1387-1396.e7DOI: (10.1016/j.jaci.2012.03.005) Copyright © 2012 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig 2 Induction of mesenchymal genes in esophageal epithelial cells in culture: evidence for EMT in vitro. Analysis of adhesion molecules and cytoskeletal component expression representative of epithelial cells (E-cadherin, cytokeratin 8, and cytokeratin 14) and mesenchymal cells (N-cadherin, vimentin, and fibronectin) in HET-1A cells after 24 and 48 hours of culture with TGF-β1 (5 ng/mL) is shown. Data are expressed as mean ± SD relative mRNA abundance compared with that in untreated control subjects, as determined by using RT-Q-PCR. Statistical significance was assessed by using the Student t test compared with untreated control subjects at 24 and 48 hours. *P < .05, **P < .01, and ***P < .001 (n = 5-7 per group). Journal of Allergy and Clinical Immunology 2012 129, 1387-1396.e7DOI: (10.1016/j.jaci.2012.03.005) Copyright © 2012 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig 3 Immunofluorescent staining for EMT in subject study groups. Immunofluorescent staining for cytokeratin (epithelial marker, green) and vimentin (mesenchymal marker, red) in the epithelium with 4′-6-diamidino-2-phenylindole dihydrochloride nuclear counterstaining (blue) is shown. Representative confocal images from esophageal biopsy specimens of subjects with EoE, indeterminate EoE, GERD, and normal esophagus are shown. Quantitative assessment of the EMT index for these subject groups is shown in Fig 4. Journal of Allergy and Clinical Immunology 2012 129, 1387-1396.e7DOI: (10.1016/j.jaci.2012.03.005) Copyright © 2012 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig 4 Quantitative assessment of EMT in subjects with EoE, GERD, and normal esophagus. Mean ± SD EMT scores for the 4 subject groups are shown. The highest EMT index was associated with EoE, followed by indeterminate EoE > GERD > normal esophagus. The mean for the normal esophagus control group was right skewed; that is, more values were closer to an EMT score of zero, whereas the mean for EoE was slightly left skewed. The level of EMT in subjects with EoE was not significantly different from that seen in the indeterminate EoE group, whereas both of these subject groups had significantly greater EMT scores than the GERD and normal esophagus groups. Comparative EMT scores for the 2 independent observers are shown in Table E2. NS, Not significant. **P < .01 and ***P < .001. Journal of Allergy and Clinical Immunology 2012 129, 1387-1396.e7DOI: (10.1016/j.jaci.2012.03.005) Copyright © 2012 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig 5 EMT scores correlate with measures of esophageal eosinophil counts and staining for EPX and with subepithelial fibrosis and staining for TGF-β. EMT scores per hpf were analyzed for relationships to subjects' peak numbers of esophageal eosinophils/hpf (top) and staining index for EPX (bottom; A) and fibrosis index (top) and TGF-β staining index (bottom; B) for all 60 subjects in the subject groups. The Pearson correlation coefficient (r) and its associated statistical significance are shown for all 60 subjects (dot plot with symbols) comprising the subject groups, including EoE (solid circles), indeterminate EoE (solid triangles), GERD (open circles), and normal esophagus (solid diamonds). The trend line for the mean indices (solid squares) is also shown (solid line). Journal of Allergy and Clinical Immunology 2012 129, 1387-1396.e7DOI: (10.1016/j.jaci.2012.03.005) Copyright © 2012 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig 6 Resolution of esophageal EMT in subjects with EoE after treatment: correlation with eosinophil load. A, The presence/amount of EMT was scored in subjects with EoE treated with 3 different modalities that reduce epithelial eosinophilic inflammation. Mean ± SD EMT scores before and after treatment are shown for all treated subjects combined (n = 18) and for individual treatment groups (n = 6 per group; see Table E3 for the percentage reduction in EMT). B, Resolution of esophageal EMT was directly correlated with the number of esophageal eosinophils before and after treatments that reduced the esophageal eosinophil burden (Rx). The correlation coefficient (r) and associated significance is shown for the relationship between all 18 EoE subjects' pretreatment and posttreatment EMT scores and peak eosinophil counts (combined n = 36). The vertical dashed line delineates pretreatment from posttreatment eosinophil counts/EMT scores (see Table E4 and Fig E3 for correlations within each of the individual treatment groups). **P < .01 and ***P < .001. Journal of Allergy and Clinical Immunology 2012 129, 1387-1396.e7DOI: (10.1016/j.jaci.2012.03.005) Copyright © 2012 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig E1 Three-point fibrosis assessment scale in esophageal biopsy specimens. Representative hematoxylin and eosin staining of esophageal mucosa. The fibrosis score (0-2) is indicated on the left, with descriptions of the scoring system on the right. Journal of Allergy and Clinical Immunology 2012 129, 1387-1396.e7DOI: (10.1016/j.jaci.2012.03.005) Copyright © 2012 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig E2 Evidence for EMT in subjects with EoE: presence of mesenchymal (vimentin-positive) cells in the hyperplastic epithelium. Tissue section from a subject with active EoE stained for cytokeratin (epithelial marker, green) and vimentin (mesenchymal marker, red) by using immunofluorescence, with 4′-6-diamidino-2-phenylindole dihydrochloride nuclear counterstaining (blue). The dashed white line delineates the epithelial basement membrane/lamina propria boundary. The white arrows show abnormally present vimentin-positive cells within a region of epithelium (E) near the basal zone showing decreased expression of cytokeratin, a characteristic feature of EMT. The green arrow indicates a rare cell stained for both vimentin and cytokeratin. There are numerous vimentin-positive cells (fibroblasts) in the lamina propria (LP). The bar indicates 20 μm in this ×630 confocal image. Journal of Allergy and Clinical Immunology 2012 129, 1387-1396.e7DOI: (10.1016/j.jaci.2012.03.005) Copyright © 2012 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig E3 The resolution of esophageal EMT correlates with the number of esophageal eosinophils before and after treatments that reduced the esophageal eosinophil burden in subjects with EoE. Pearson correlation analysis (r) and associated significance (P value) are shown for EMT scores versus peak eosinophil counts (n = 6 pretreatment and n = 6 posttreatment values in each group) for subjects treated with swallowed corticosteroids (A), SFED (B), and ED (C). The vertical dashed lines delineate pretreatment (right of line) from posttreatment (left of line) eosinophil counts/EMT scores. Journal of Allergy and Clinical Immunology 2012 129, 1387-1396.e7DOI: (10.1016/j.jaci.2012.03.005) Copyright © 2012 American Academy of Allergy, Asthma & Immunology Terms and Conditions