New genetic links in eosinophilic esophagitis
© BioMed Central Ltd 2010
Published: 7 September 2010
Eosinophilic esophagitis (EoE) is increasingly diagnosed as a disorder throughout the world. It is characterized by eosinophils in the esophagus due to food allergies. Molecular analysis of esophageal biopsies and mouse models have indicated a clear role for the T helper 2 pathway, in particular interleukins 5 and 13, in this disease. Current treatment options for EoE involve avoidance of the allergens or using anti-inflammatory medications such as topical corticosteroids. In the past year, genomic research has led to the identification of single nucleotide polymorphisms in the gene encoding thymic stromal lymphopoietin (TSLP), and subsequently in the gene encoding its receptor, as disease susceptibility markers for EoE. Identification of this molecule and its receptor suggest the potential for new treatment options in the future.
Definition and prevalence of eosinophilic esophagitis
Eosinophilic gastrointestinal diseases are increasingly recognized and diagnosed disorders that include eosinophilic esophagitis (EoE), eosinophilic gastroenteritis and eosinophilic colitis. Among the eosinophilic gastrointestinal diseases, EoE has become increasingly prevalent in the United States, Switzerland and Australia . Overall, EoE is a global health condition now reported on all continents except Africa, with an incidence of approximately 5 in 10,000 [1, 2].
The diagnosis of EoE is based on clinicopathology and depends in part on demonstration of esophageal eosinophilia. A panel of experts proposed consensus recommendations in 2007 , which included the demonstration of 15 or more eosinophils in at least one high-powered field despite treatment with a proton pump inhibitor or exclusion of gastroesophageal reflux disease (GERD) by ambulatory pH monitoring. The clinical presentation of EoE varies with age: infants and toddlers often have difficulty feeding and fail to thrive, school-age children present with vomiting and epigastric or chest pain, and adolescents and adults present with dysphagia and food impaction .
EoE is considered a food-allergy-related disorder on the basis of several findings. Most patients are atopic individuals (that is, they have a high rate of food allergen sensitization as determined using skin prick and patch testing); in addition, EoE patients have a higher rate of food anaphylaxis than the general population . Moreover, nearly all EoE patients have complete remission following introduction of an elemental formula diet that removes all allergens from the diet; conversely, the disease flares on reintroduction of specific foods . Unlike classic anaphylaxis that typically involves a limited set of foods, EoE patients are often sensitized to a myriad of foods, often including food groups not typically considered to elicit anaphylaxis .
Mechanism of eosinophilic esophagitis
EoE seems to be similar to many other allergic diseases with a mechanism of disease mediated by T helper 2 (Th2) cells. Experimental mouse models have demonstrated key roles for adaptive immunity, Th2 cell cytokines (especially interleukin (IL)-5 and IL-13) and eosinophilic-attraction chemokines such as CCL26 (also called eotaxin-3) in the development of EoE, and also a strong connection between allergic sensitization and inflammation in the respiratory tract and skin [5, 6]. IL-13 has been shown to induce many of the features of EoE in human tissue and murine systems, including the induction of CCL-26 . Genome-wide profiling revealed that CCL-26 is overexpressed about 50-fold compared with normal controls or patients with GERD . In addition, Rothenberg and colleagues  found that the EoE transcriptome was consistent across sex, age and familial or non-familial inheritance patterns and was independent of atopic status, suggesting a common disease mechanism despite phenotypic variations. A potential proposed mechanism is that Th2 cell activation leads to overexpression of CCL-26 and thereby to migration of eosinophils to the esophagus.
Work by Aceves and colleagues  showed that eosinophilic migration and activation in EoE lead to subepithelial fibrosis and to increased expression of transforming growth factor β (TGF-β) and its downstream signaling molecule phospho-SMAD2/3 compared with patients with GERD and healthy controls. In addition, esophageal biopsies demonstrated an increased expression of vascular cell adhesion molecule 1 (VCAM-1) . This fibrosis may account for the esophageal dysmotility that leads to the symptoms of dysphagia and food impaction observed in adults. The chronic fibrosis and changes in inflammatory markers also parallel symptoms observed in asthma.
Genetic links in EoE
The evidence indicates that EoE has a strong familial association, with nearly 10% of parents of EoE patients having a history of esophageal strictures and about 8% having biopsy-proven EoE . EoE also shows a high sibling risk ratio (λS) of approximately 80 compared with related atopic diseases such as asthma (λS about 2) . The first candidate gene for EoE identified was CCL-26, the most overexpressed gene in the esophagus as determined by genome-wide expression profiling . However, the disease-associated allele is present in only 14% of EoE patients .
Rather than looking at the potential pathways, Aceves and colleagues  examined response to topical corticosteroids - a standard therapy for the condition - in patients with EoE. A positive response was defined as residual eosinophil counts of seven or fewer eosinophils per high-power field. Responders had a reduced esophageal remodeling with decreased fibrosis, fewer TGF-β- and pSmad2/3-positive cells and decreased vascular activation following therapy with the corticosteroid budesonide. Responders were more likely to have a CC genotype at the -509 position in the TGF-β promoter than were non-responders.
More recently, a multi-center genome-wide association study (GWAS) has identified the thymic stromal lymphopoietin (TSLP) gene, at 5q22, as an important candidate gene in the pathogenesis of the disease . TSLP is an epithelial-derived cytokine that activates professional antigen-presenting cells, such as dendritic cells, which initiate Th2-type allergic responses . The same study also found an increased expression of TSLP in the esophagi of patients with EoE compared with healthy controls .
The most recent finding by Sherrill et al.  adds to our understanding of the interaction of TSLP and EoE. This genomic analysis  focused on key allergic single nucleotide polymorphisms (SNPs) along with epithelial SNPs and compared them in atopic and healthy controls. In addition to replicating the significant association between SNPs at TSLP and EoE, they found that TSLP variants remained significant when compared with atopic controls in their study  or asthma controls from the previous GWAS analysis . However, variations in the TSLP gene were not significant when compared with controls, probably because of the small number of controls used. TSLP has also been found to be associated with atopic dermatitis  and asthma  compared with healthy controls. The finding of TSLP being significant only among the atopic controls could be due either to the other studies not removing patients with EoE (which is commonly atopic) from their control group or to the possibility that TSLP might trigger multiple atopic diseases depending on secondary signals.
Sherrill and colleagues  also found a SNP in the TSLP receptor (TSLPR) gene that was associated with EoE. The gene encoding the TSLP receptor is located on the pseudoautosomal region on Xp22.3 and Yp11.3 and it was significantly associated with disease only in male patients with EoE. Given that EoE is more common among males by a 2:1 ratio , the finding of a SNP in the TSLPR suggests a potential mechanism for the male dominance observed in EoE. Sherrill et al.  also noted one additional finding that may suggest alternative pathways for the treatment or the pathogenesis of EoE: they observed that stimulation of primary esophageal epithelial cells with poly I:C (a double-stranded RNA mimetic) induced the expression of TSLP mRNA. This induction was dependent on Toll-like receptor (TLR)-3 stimulation. TLR-3 recognizes double-stranded RNA, which is found in some viruses such as reoviruses. These results suggest a second hit for the development of EoE with a viral trigger and allergen exposure. In the lung and skin TSLP is produced primarily by epithelial cells in response to Th2 cytokines or TLR3 agonists, and it subsequently targets dendritic cells to secrete Th2-inducing activity, including Th2 cytokine and chemokine production.
These findings  suggest a unique potential mechanism for the induction of EoE. Could food allergens trigger the TLR-3 receptor, inducing TSLP and causing the activation of the Th2 pathway, leading to eosinophilic inflammation in the esophagus? Or is there a 'second hit', a virus that makes susceptible people develop EoE?
Potential pathways for treatment
The current treatment options for EoE involve the avoidance of the trigger (foods) and the treatment of the underlying inflammation with topical corticosteroids . Treatment with food avoidance is highly successful, with rates close to 100% with elemental diets (amino acid formulas) . However, these formulas are unpalatable and lead to low quality of life. Eliminating foods on the basis of allergy testing or empirical elimination leads to resolution of esophageal eosinophilia in 50 to 80% of patients, depending on the diet and the age of the patient and reduction of symptoms in over 90% of the patients . These diets are also difficult to maintain and many patients refuse to continue them. Treatment with topical steroids can work for 50 to 80% of patients, but there are also some drawbacks. Topical corticosteroids can lead to localized yeast infections and have potential long-term side effects, including growth suppression and osteopenia (low bone density); however, these have not been studied or seen in short-term studies. Other treatments currently being investigated include anti-immunoglobulin (Ig)E, anti-IL-5, anti-IL-13 and chemoattractant homologous receptor expressed on Th2 cells (CRTH2) antagonist or topical corticosteroids [16–18].
The recent identification of TSLP and its receptor as key components in the EoE pathogenesis  suggests that blockage of the TSLP-TSLP receptor activation could provide an attractive approach to treating the cause of EoE. In addition, the new finding that TLR-3 induces TSLP suggests that a second hit (a virus) may trigger this pathway. If a particular virus or microorganism unique for EoE were identified, this would allow the development of a preventive strategy. This is unlikely to occur in the near future, but treatment with TLR-3 antagonists or blocking downstream signaling already represent hope for the treatment of EoE.
chemokine (C-C motif) ligand 26
genome-wide association study
gastroesophageal reflux disease
single nucleotide polymorphism
transforming growth factor
T helper 2
thymic stromal lymphopoietin.
Work in the author's laboratory is funded by Cephalon, the NIH and Department of Defense.
- Furuta GT, Liacouras CA, Collins MH, Gupta SK, Justinich C, Putnam PE, Bonis P, Hassall E, Straumann A, Rothenberg ME: Eosinophilic esophagitis in children and adults: a systematic review and consensus recommendations for diagnosis and treatment. Gastroenterology. 2007, 133: 1342-1363. 10.1053/j.gastro.2007.08.017.PubMedView ArticleGoogle Scholar
- Spergel JM, Book W, Mays E, Song L, Shah S, Talley N, Bonis P: Variation in prevalence and practice styles for eosinophilic gastrointestinal diseases in the United States. J Pediatr Gastroenterol Nutr.
- Spergel JM, Brown-Whitehorn TF, Beausoleil JL, Franciosi J, Shuker M, Verma R, Liacouras CA: 14 years of eosinophilic esophagitis: clinical features and prognosis. J Pediatr Gastroenterol Nutr. 2009, 48: 30-36. 10.1097/MPG.0b013e3181788282.PubMedView ArticleGoogle Scholar
- Jyonouchi S, Brown-Whitehorn TA, Spergel JM: Association of eosinophilic gastrointestinal disorders with other atopic disorders. Immunol Allergy Clin North Am. 2009, 29: 85-97. 10.1016/j.iac.2008.09.008.PubMedView ArticleGoogle Scholar
- Blanchard C, Rothenberg ME: Basic pathogenesis of eosinophilic esophagitis. Gastrointest Endosc Clin N Am. 2008, 18: 133-143. 10.1016/j.giec.2007.09.016. xPubMedPubMed CentralView ArticleGoogle Scholar
- Blanchard C, Wang N, Stringer KF, Mishra A, Fulkerson PC, Abonia JP, Jameson SC, Kirby C, Konikoff MR, Collins MH, Cohen MB, Akers R, Hogan SP, Assa'ad AH, Putnam PE, Aronow BJ, Rothenberg ME: Eotaxin-3 and a uniquely conserved gene-expression profile in eosinophilic esophagitis. J Clin Invest. 2006, 116: 536-547. 10.1172/JCI26679.PubMedPubMed CentralView ArticleGoogle Scholar
- Blanchard C, Mingler MK, Vicario M, Abonia JP, Wu YY, Lu TX, Collins MH, Putnam PE, Wells SI, Rothenberg ME: IL-13 involvement in eosinophilic esophagitis: transcriptome analysis and reversibility with glucocorticoids. J Allergy Clin Immunol. 2007, 120: 1292-1300. 10.1016/j.jaci.2007.10.024.PubMedView ArticleGoogle Scholar
- Aceves SS, Newbury RO, Dohil R, Bastian JF, Broide DH: Esophageal remodeling in pediatric eosinophilic esophagitis. J Allergy Clin Immunol. 2007, 119: 206-212. 10.1016/j.jaci.2006.10.016.PubMedView ArticleGoogle Scholar
- Malerba G, Lauciello MC, Scherpbier T, Trabetti E, Galavotti R, Cusin V, Pescollderungg L, Zanoni G, Martinati LC, Boner AL, Levitt RC, Pignatti PF: Linkage analysis of chromosome 12 markers in Italian families with atopic asthmatic children. Am J Respir Crit Care Med. 2000, 162: 1587-1590.PubMedView ArticleGoogle Scholar
- Aceves SS, Newbury RO, Chen D, Mueller J, Dohil R, Hoffman H, Bastian JF, Broide DH: Resolution of remodeling in eosinophilic esophagitis correlates with epithelial response to topical corticosteroids. Allergy. 2010, 65: 109-116. 10.1111/j.1398-9995.2009.02142.x.PubMedPubMed CentralView ArticleGoogle Scholar
- Rothenberg ME, Spergel JM, Sherrill JD, Annaiah K, Martin LJ, Cianferoni A, Gober L, Kim C, Glessner J, Frackelton E, Thomas K, Blanchard C, Liacouras C, Verma R, Aceves S, Collins MH, Brown-Whitehorn T, Putnam PE, Franciosi JP, Chiavacci RM, Grant SF, Abonia JP, Sleiman PM, Hakonarson H: Common variants at 5q22 associate with pediatric eosinophilic esophagitis. Nat Genet. 2010, 42: 289-291. 10.1038/ng.547.PubMedPubMed CentralView ArticleGoogle Scholar
- Liu YJ: TSLP in epithelial cell and dendritic cell cross talk. Adv Immunol. 2009, 101: 1-25. full_text.PubMedPubMed CentralView ArticleGoogle Scholar
- Sherrill JD, Gao P, Stucke EM, Blanchard C, Collins MH, Putman PE, Franciosi JP, Kushner JP, Abonia JP, Assa'ad AH, Kovacic MB, Biagini JM, Bochner BS, He H, Hershey GK, Martin LJ, Rothenberg ME: Variants of thymic stromal lymphopoietin and its receptor associate with eosinophilic esophagitis. J Allergy Clin Immunol. 2010, 126: 160-165. 10.1016/j.jaci.2010.04.037.PubMedPubMed CentralView ArticleGoogle Scholar
- Gao PS, Rafaels NM, Mu D, Hand T, Murray T, Boguniewicz M, Hata T, Schneider L, Hanifin JM, Gallo RL, Gao L, Beaty TH, Beck LA, Leung DY, Barnes KC: Genetic variants in thymic stromal lymphopoietin are associated with atopic dermatitis and eczema herpeticum. J Allergy Clin Immunol. 2010, 125: 1403-1407. 10.1016/j.jaci.2010.03.016. e4PubMedPubMed CentralView ArticleGoogle Scholar
- He JQ, Hallstrand TS, Knight D, Chan-Yeung M, Sandford A, Tripp B, Zamar D, Bosse Y, Kozyrskyj AL, James A, Laprise C, Daley D: A thymic stromal lymphopoietin gene variant is associated with asthma and airway hyperresponsiveness. J Allergy Clin Immunol. 2009, 124: 222-229. 10.1016/j.jaci.2009.04.018.PubMedView ArticleGoogle Scholar
- NCT01056783: Proof of Concept Study of OC000459 in Eosinophilic Esophagitis. [http://clinicaltrials.gov/ct2/show/NCT01056783]
- NCT00638456: Use of Topical Budesonide in the Treatment of Eosinophilic Esophagitis. [http://clinicaltrials.gov/ct2/show/NCT00638456?term=NCT00638456]
- NCT00538434: Efficacy and Safety Study of Reslizumab to Treat Eosinophilic Esophagitis in Subjects Aged 5 to 18 Years. [http://clinicaltrials.gov/ct2/show/NCT00538434?term=NCT00538434]