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Expression of mast cell–associated genes is upregulated in adult eosinophilic esophagitis and responds to steroid or dietary therapy

2011; Elsevier BV; Volume: 127; Issue: 5 Linguagem: Inglês

10.1016/j.jaci.2010.12.1118

1097-6825

Karen S. Hsu Blatman, Nirmala Gonsalves, Ikuo Hirano, Paul Bryce,

IL-33, ST2, and ILC Pathways

To the Editor: Eosinophilic esophagitis (EoE) is an eosinophil-dominated disease seen in the esophagi of both children and adults. Despite many similarities, differences exist between pediatric and adult EoE. Adults with EoE typically present with dysphagia and food impaction, whereas children present with failure to thrive or vomiting.1Rothenberg M.E. Biology and treatment of eosinophilic esophagitis.Gastroenterology. 2009; 137: 1238-1249Abstract Full Text Full Text PDF PubMed Scopus (257) Google Scholar Patients with EoE often have a personal and family history of atopic disease. We previously reported differences in the patterns of allergic predisposition between adult and pediatric EoE.2Gonsalves N. Anh T. Zhang Q. Kagalwalla A. Ditto A. Hirano I. Distinct allergic predisposition of children and adults with Eosinophilic Esophagitis.Gastroenterology. 2006; 130: A579Google Scholar Adults with EoE often have specific IgE for food allergens, aeroallergens, or both but rarely have a history of food-induced anaphylaxis.1Rothenberg M.E. Biology and treatment of eosinophilic esophagitis.Gastroenterology. 2009; 137: 1238-1249Abstract Full Text Full Text PDF PubMed Scopus (257) Google Scholar Although the role of eosinophils in EoE is well established, that of mast cells is less clear.3Lucendo A.J. Bellon T. Lucendo B. The role of mast cells in eosinophilic esophagitis.Pediatr Allergy Immunol. 2009; 20: 512-518Crossref PubMed Scopus (37) Google Scholar, 4Wershil B.K. Exploring the role of mast cells in eosinophilic esophagitis.Immunol Allergy Clin North Am. 2009; 29 (xiii): 189-195Abstract Full Text Full Text PDF PubMed Scopus (14) Google Scholar In 2001, Straumann et al5Straumann A. Bauer M. Fischer B. Blaser K. Simon H.U. Idiopathic eosinophilic esophagitis is associated with a T(H)2-type allergic inflammatory response.J Allergy Clin Immunol. 2001; 108: 954-961Abstract Full Text Full Text PDF PubMed Scopus (486) Google Scholar identified increased mast cell numbers in adults with EoE.5Straumann A. Bauer M. Fischer B. Blaser K. Simon H.U. Idiopathic eosinophilic esophagitis is associated with a T(H)2-type allergic inflammatory response.J Allergy Clin Immunol. 2001; 108: 954-961Abstract Full Text Full Text PDF PubMed Scopus (486) Google Scholar However, despite much discussion, the roles for mast cells in patients with EoE have not been defined.4Wershil B.K. Exploring the role of mast cells in eosinophilic esophagitis.Immunol Allergy Clin North Am. 2009; 29 (xiii): 189-195Abstract Full Text Full Text PDF PubMed Scopus (14) Google Scholar Recently, studies by Abonia et al6Abonia J.P. Blanchard C. Butz B.B. Rainey H.F. Collins M.H. Stringer K. et al.Involvement of mast cells in eosinophilic esophagitis.J Allergy Clin Immunol. 2010; 126: 140-149Abstract Full Text Full Text PDF PubMed Scopus (224) Google Scholar and Aceves et al7Aceves S.S. Chen D. Newbury R.O. Dohil R. Bastian J.F. Broide D.H. Mast cells infiltrate the esophageal smooth muscle in patients with eosinophilic esophagitis, express TGF-beta1, and increase esophageal smooth muscle contraction.J Allergy Clin Immunol. 2010; 126 (e4): 1198-1204Abstract Full Text Full Text PDF PubMed Scopus (202) Google Scholar have defined an involvement of mast cells in pediatric EoE. We have concurrently been investigating mast cells in adult EoE. Our results in adults with EoE, described in this article, now support the findings of Abonia et al6Abonia J.P. Blanchard C. Butz B.B. Rainey H.F. Collins M.H. Stringer K. et al.Involvement of mast cells in eosinophilic esophagitis.J Allergy Clin Immunol. 2010; 126: 140-149Abstract Full Text Full Text PDF PubMed Scopus (224) Google Scholar and implicate mast cells in the pathogenesis of both pediatric and adult EoE. Biopsy specimens from the distal esophagus were collected from adult patients undergoing upper endoscopy for evaluation of dysphagia. Biopsy specimens from 7 patients without EoE (3 male and 4 female patients; median age, 54 years; age range, 27-80 years; average peak eosinophil count, 0) and from 21 patients with EoE (17 male and 4 female patients; median age, 40 years; age range, 28-84 years; average peak eosinophil count, 41.3) were studied for expression of several well-defined mast cell–associated genes: the β chain of the high-affinity IgE receptor (FCERIB), the histamine-synthesizing enzyme histidine decarboxylase (HDC), and 2 mast cell–specific proteases: tryptase α/β1 (TPSAB1) and carboxypeptidase (CPA3). All patients displayed panesophageal endoscopic and histological features, and biopsy specimens from both the proximal and distal sites were taken, as is standard practice at our institution. Initial studies demonstrated similar expression profiles between both locations, and therefore only distal biopsy specimens are reported here. In addition, we investigated the expression in biopsy specimens from additional patients with EoE who had undergone therapy with either swallowed fluticasone (440 μg administered twice daily, n = 5) or patients undergoing treatment with a standardized empiric food elimination diet8Kagalwalla A.F. Sentongo T.A. Ritz S. Hess T. Nelson S.P. Emerick K.M. et al.Effect of six-food elimination diet on clinical and histologic outcomes in eosinophilic esophagitis.Clin Gastroenterol Hepatol. 2006; 4: 1097-1102Abstract Full Text Full Text PDF PubMed Scopus (587) Google Scholar of 8 foods: milk, egg, soy, peanut, tree nut, wheat, shellfish, and fish. This group included patients who responded initially after the 6-week empiric elimination diet (n = 6), those who continued to respond during food reintroduction (n = 6), and those who underwent relapse on food reintroduction (n = 9). Esophageal biopsy specimens were taken before dietary therapy and after the initial 6-week diet. The 8 food groups were reintroduced one group at a time every 2 weeks, with follow-up endoscopies every 4 weeks with biopsies. Gene expression was determined by using Taqman real-time RT-PCR, and the Institutional Review Board of Northwestern University approved this study. Further classification and methods are available in this article's Online Repository at www.jacionline.org. Atopic clinical history was common in our patients with EoE (85% with a history of allergic rhinitis or asthma), which is consistent with prior studies.1Rothenberg M.E. Biology and treatment of eosinophilic esophagitis.Gastroenterology. 2009; 137: 1238-1249Abstract Full Text Full Text PDF PubMed Scopus (257) Google Scholar, 2Gonsalves N. Anh T. Zhang Q. Kagalwalla A. Ditto A. Hirano I. Distinct allergic predisposition of children and adults with Eosinophilic Esophagitis.Gastroenterology. 2006; 130: A579Google Scholar, 9Gonsalves N. Policarpio-Nicolas M. Zhang Q. Rao M.S. Hirano I. Histopathologic variability and endoscopic correlates in adults with eosinophilic esophagitis.Gastrointest Endosc. 2006; 64: 313-319Abstract Full Text Full Text PDF PubMed Scopus (394) Google Scholar However, at the initial visit, no patients were receiving treatment with systemic or swallowed topical steroids, food elimination diet, or elemental diet. Eight-five percent of the patients were undergoing therapy with proton pump inhibitors at the time of index endoscopy with biopsy. Compared with those from control subjects, biopsy specimens from patients with EoE without treatment had significant increases in expression of mast cell genes for FCERIB (P < .05), HDC (P < .01), TPSAB1 (P < .01), and CPA3 (P < .01), as determined by using Student t test comparisons. Similar to the findings in pediatric EoE, mast cell–associated gene expression was significantly reduced by treatment with swallowed fluticasone (Fig 1). One patient was found to be nonresponsive on swallowed fluticasone twice daily but did respond to systemic steroids, and mast cell–associated gene expression decreased to levels similar to those seen in the swallowed fluticasone group (data not shown). Gene expression for FCERIB, HDC, TPSAB1, and CPA3 was also significantly reduced by the 8-food elimination diet (Fig 2). Gene expression remained decreased during food reintroduction when patients denied any symptoms. Conversely, expression of these genes remained increased in nonresponders and was increased in those patients experiencing food reintroduction–induced relapse. Expression of stem cell factor was similarly affected (see this article's Fig E1 in the Online Repository at www.jacionline.org). Eotaxin-3 (CCL26) is highly expressed in pediatric EoE10Blanchard C. Wang N. Stringer K.F. Mishra A. Fulkerson P.C. Abonia J.P. et al.Eotaxin-3 and a uniquely conserved gene-expression profile in eosinophilic esophagitis.J Clin Invest. 2006; 116: 536-547Crossref PubMed Scopus (724) Google Scholar and correlated with CPA3 expression in pediatric EoE.6Abonia J.P. Blanchard C. Butz B.B. Rainey H.F. Collins M.H. Stringer K. et al.Involvement of mast cells in eosinophilic esophagitis.J Allergy Clin Immunol. 2010; 126: 140-149Abstract Full Text Full Text PDF PubMed Scopus (224) Google Scholar In our adult samples eotaxin-3 was also highly expressed compared with that seen in control samples (data not shown) and also correlated with CPA3 expression (r = 0.58; P < .05, Spearman correlation; Fig 3). A similar correlation was seen with HDC and TPSAB1 also (see this article's Fig E2 in the Online Repository at www.jacionline.org). In summary, our data suggest that adult EoE is associated with local upregulation of mast cell responses and that these alterations are highly responsive to therapy with either steroids or a food elimination diet. Our study supports the recent studies demonstrating mastocytosis in esophageal biopsy tissue.5Straumann A. Bauer M. Fischer B. Blaser K. Simon H.U. Idiopathic eosinophilic esophagitis is associated with a T(H)2-type allergic inflammatory response.J Allergy Clin Immunol. 2001; 108: 954-961Abstract Full Text Full Text PDF PubMed Scopus (486) Google Scholar, 6Abonia J.P. Blanchard C. Butz B.B. Rainey H.F. Collins M.H. Stringer K. et al.Involvement of mast cells in eosinophilic esophagitis.J Allergy Clin Immunol. 2010; 126: 140-149Abstract Full Text Full Text PDF PubMed Scopus (224) Google Scholar The upregulation of mast cell–associated gene expression and its responsiveness to therapy and correlation with disease reoccurrence on food-induced relapse indicate that mast cells likely participate in the pathogenesis of EoE. Consequently, mast cells might be an important target for treatment of both pediatric and adult disease. All patients who were characterized as having EoE had undergone either a 4- to 6-week course of twice-daily proton pump inhibition before index endoscopy or had documented negative acid exposure determined by means of pH probe, as per current consensus guidelines. Patients were grouped according to the following criteria: Control subjects: Evaluated for dysphagia but did not have EoE based on a lack of endoscopic features and absence of eosinophils in biopsy specimens. Patients with EoE: Reported symptoms, endoscopic features (rings, furrows, and/or strictures), and more than 15 eosinophils per high-power field on biopsy. EoE response: Resolution of reported symptoms and less than 15 eosinophils per high-power field on biopsy. EoE nonresponse: Continuation of reported symptoms and more than 15 eosinophils per high-power field on biopsy. EoE recurrence: On food reintroduction, return of symptoms and more than 15 eosinophils per high-power field on biopsy. Total RNA was isolated from distal esophageal tissue with an RNeasy kit (Qiagen, Valencia, Calif). cDNA was prepared by using qScript cDNA Super Mix (Quanta, Gaithersburg, Md). Gene expression was determined by means of PCR with an ABI 7500 Thermal cycler (Applied Biosystems, Foster City, Calif) and specific Taqman probes (Applied Biosystems) for each gene of interest. Gene expression was determined based on the change in cycle threshold value (ΔCt) between the gene of interest and the glyceraldehyde-3-phosphate dehydrogenase gene (GAPDH), as previously described.E1 Data represent the 2-ΔCt value for each sample.