Clinical Reviews in Allergy & Immunology

, Volume 55, Issue 1, pp 19–42 | Cite as

Pathophysiology of Eosinophilic Esophagitis

  • Benjamin P. DavisEmail author


Eosinophilic esophagitis (EoE) is a chronic inflammatory disease of the esophagus associated with an atopic predisposition which appears to be increasing in prevalence over the last few decades. Symptoms stem from fibrosis, swelling, and smooth muscle dysfunction. In the past two decades, the etiology of EoE has been and is continuing to be revealed. This review provides an overview of the effects of genetics, environment, and immune function including discussions that touch on microbiome, the role of diet, food allergy, and aeroallergy. The review further concentrates on the pathophysiology of the disease with particular focus on the important concepts of the molecular etiology of EoE including barrier dysfunction and allergic hypersensitivity.


Aeroallergy Basophil Epithelial-to-mesenchymal transition Eosinophilic esophagitis Eosinophil Esophagus Esophagitis Food allergy Innate lymphoid cells Invariant natural killer T cells Microbiome Squamous epithelium 



Atopic dermatitis


Absolute eosinophil count


Air-liquid interface


Arachidonate-15 lipooxygenase


Antigen-presenting cells


Atopy patch test


Calpain 14


Cadherin-like 26


Carboxypeptidase 3A


Cytokine receptor–like factor 2


Chronic rhinosinusitis


Chemoattractant receptor expressed on Th2 cells


Connective tissue disorders


Dedicator Of cytokinesis 8


Desmoglein 1


Eosinophil cationic protein


Epidermal differentiation complex


EoE diagnostic panel


Electronic medical record


Epithelial-to-mesenchymal transition


Eosinophilic esophagitis


Eosinophil peroxidase


Eosinophil peroxidase


Esophageal string test


IgE Fragment crystallizable epsilon receptor 1




Gastroesophageal reflux disease


Genome-wide association studies


High-power field


Inflammatory bowel disease






Innate lymphoid cells


Invariant natural killer T cells




Loetyz-Dietz syndrome


Major basic protein


Macrophage migration inhibitory factor


Macrophage inflammatory protein 1




Oral immunotherapy


Plasminogen activator inhibitor-1


Prostaglandin D2


PTEN hamartoma tumor syndrome




PPI-responsive esophageal eosinophilia


Proton pump inhibitor




Regulated on activation, normal T cells expressed and secreted


Severe dermatitis, multiple allergies, and metabolic wasting


Serine protease inhibitors


Serine protease inhibitors, Kazal type


Small proline-rich repeat


Skin prick test


Signal transducer and activator of transcription


Transforming growth factor beta


T helper type


Tumor necrosis factor-α




TNF-related apoptosis-inducing ligand


T regulatory cells


Thymic stromal lymphopoietin


Tissue transglutaminase


Tyrosine-protein kinase-2


Ulcerative colitis


Uroplakin 1B



No funding was used in the creation of this manuscript.

Compliance with Ethical Standards

Conflicts of Interest

The author has no conflicts of interest.

Ethical Approval

The accepted principles of ethical and professional conduct were followed in the creation of this manuscript.

Informed Consent

No human subjects were a part of this manuscript.


  1. 1.
    Abonia JP, Rothenberg ME (2012) Eosinophilic esophagitis: rapidly advancing insights. Annu Rev Med 63(1):421–434. PubMedCrossRefGoogle Scholar
  2. 2.
    Jensen ET, Kappelman MD, Martin CF, Dellon ES (2015) Health-care utilization, costs, and the burden of disease related to eosinophilic esophagitis in the United States. Am J Gastroenterol 110(5):626–632. PubMedCrossRefGoogle Scholar
  3. 3.
    Eder W, Ege MJ, von Mutius E (2006) The asthma epidemic. N Engl J Med 355(21):2226–2235. PubMedCrossRefGoogle Scholar
  4. 4.
    DeBrosse CW, Collins MH, Buckmeier Butz BK, Allen CL, King EC, Assa'ad AH, Abonia JP, Putnam PE, Rothenberg ME, Franciosi JP (2010) Identification, epidemiology, and chronicity of pediatric esophageal eosinophilia, 1982-1999. J Allergy Clin Immunol 126(1):112–119. PubMedPubMedCentralCrossRefGoogle Scholar
  5. 5.
    Noel RJ, Putnam PE, Rothenberg ME (2004) Eosinophilic esophagitis. N Engl J Med 351(9):940–941. PubMedCrossRefGoogle Scholar
  6. 6.
    Sherrill JD, Rothenberg ME (2014) Genetic and epigenetic underpinnings of eosinophilic esophagitis. Gastroenterol Clin N Am 43(2):269–280. CrossRefGoogle Scholar
  7. 7.
    Liacouras CA, Furuta GT, Hirano I, Atkins D, Attwood SE, Bonis PA, Burks AW, Chehade M, Collins MH, Dellon ES, Dohil R, Falk GW, Gonsalves N, Gupta SK, Katzka DA, Lucendo AJ, Markowitz JE, Noel RJ, Odze RD, Putnam PE, Richter JE, Romero Y, Ruchelli E, Sampson HA, Schoepfer A, Shaheen NJ, Sicherer SH, Spechler S, Spergel JM, Straumann A, Wershil BK, Rothenberg ME, Aceves SS (2011) Eosinophilic esophagitis: updated consensus recommendations for children and adults. J Allergy Clin Immunol 128(1):3–20 e26; quiz 21-22. PubMedCrossRefPubMedCentralGoogle Scholar
  8. 8.
    Wen T, Dellon ES, Moawad FJ, Furuta GT, Aceves SS, Rothenberg ME (2015) Transcriptome analysis of proton pump inhibitor-responsive esophageal eosinophilia reveals proton pump inhibitor-reversible allergic inflammation. J Allergy Clin Immunol 135(1):187–197. PubMedCrossRefGoogle Scholar
  9. 9.
    Davis BP, Rothenberg ME (2013) Emerging concepts of dietary therapy for pediatric and adult eosinophilic esophagitis. Expert Rev Clin Immunol 9(4):285–287. PubMedCrossRefGoogle Scholar
  10. 10.
    Arias A, Carrera-Parra LF (2014) First record of the genus Kuwaita (Annelida: Lumbrineridae) in Europe with the description of a new species and new ultramorphological data for the genus. Zootaxa 3887(1):68–78. PubMedCrossRefGoogle Scholar
  11. 11.
    Ally MR, Dias J, Veerappan GR, Maydonovitch CL, Wong RK, Moawad FJ (2013) Safety of dilation in adults with eosinophilic esophagitis. Dis Esophagus 26(3):241–245. PubMedCrossRefGoogle Scholar
  12. 12.
    Spergel JM, Brown-Whitehorn TF, Beausoleil JL, Franciosi J, Shuker M, Verma R, Liacouras CA (2009) 14 years of eosinophilic esophagitis: clinical features and prognosis. J Pediatr Gastroenterol Nutr 48(1):30–36. PubMedCrossRefGoogle Scholar
  13. 13.
    DeBrosse CW, Franciosi JP, King EC, Butz BK, Greenberg AB, Collins MH, Abonia JP, Assa'ad A, Putnam PE, Rothenberg ME (2011) Long-term outcomes in pediatric-onset esophageal eosinophilia. J Allergy Clin Immunol 128(1):132–138. PubMedPubMedCentralCrossRefGoogle Scholar
  14. 14.
    Abonia JP, Wen T, Stucke EM, Grotjan T, Griffith MS, Kemme KA, Collins MH, Putnam PE, Franciosi JP, von Tiehl KF, Tinkle BT, Marsolo KA, Martin LJ, Ware SM, Rothenberg ME (2013) High prevalence of eosinophilic esophagitis in patients with inherited connective tissue disorders. J Allergy Clin Immunol 132(2):378–386. PubMedCrossRefGoogle Scholar
  15. 15.
    Sherrill JD, Rothenberg ME (2011) Genetic dissection of eosinophilic esophagitis provides insight into disease pathogenesis and treatment strategies. J Allergy Clin Immunol 128(1):23–32; quiz 33-24. PubMedPubMedCentralCrossRefGoogle Scholar
  16. 16.
    Blanchard C (2006) Eotaxin-3 and a uniquely conserved gene-expression profile in eosinophilic esophagitis. J Clin Investig 116(2):536–547. PubMedCrossRefGoogle Scholar
  17. 17.
    Blanchard C, Stucke EM, Burwinkel K, Caldwell JM, Collins MH, Ahrens A, Buckmeier BK, Jameson SC, Greenberg A, Kaul A, Franciosi JP, Kushner JP, Martin LJ, Putnam PE, Abonia JP, Wells SI, Rothenberg ME (2010) Coordinate interaction between IL-13 and epithelial differentiation cluster genes in eosinophilic esophagitis. J Immunol 184(7):4033–4041. PubMedCrossRefGoogle Scholar
  18. 18.
    Aceves SS, Newbury RO, Chen D, Mueller J, Dohil R, Hoffman H, Bastian JF, Broide DH (2010) Resolution of remodeling in eosinophilic esophagitis correlates with epithelial response to topical corticosteroids. Allergy 65(1):109–116. PubMedCrossRefGoogle Scholar
  19. 19.
    Sherrill JD, Gao P-S, Stucke EM, Blanchard C, Collins MH, Putnam PE, Franciosi JP, Kushner JP, Abonia JP, Assa'ad AH, Kovacic MB, Biagini Myers JM, Bochner BS, He H, Hershey GK, Martin LJ, Rothenberg ME (2010) Variants of thymic stromal lymphopoietin and its receptor associate with eosinophilic esophagitis. J Allergy Clin Immunol 126(1):160–165.e163. PubMedPubMedCentralCrossRefGoogle Scholar
  20. 20.
    Sleiman PMA, Wang M-L, Cianferoni A, Aceves S, Gonsalves N, Nadeau K, Bredenoord AJ, Furuta GT, Spergel JM, Hakonarson H (2014) GWAS identifies four novel eosinophilic esophagitis loci. Nat Commun 5:5593. PubMedPubMedCentralCrossRefGoogle Scholar
  21. 21.
    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 SFA, Abonia JP, Sleiman PMA, Hakonarson H (2010) Common variants at 5q22 associate with pediatric eosinophilic esophagitis. Nat Genet 42(4):289–291. PubMedPubMedCentralCrossRefGoogle Scholar
  22. 22.
    Patel ZH, Kottyan LC, Lazaro S, Williams MS, Ledbetter DH, Tromp H, Rupert A, Kohram M, Wagner M, Husami A, Qian Y, Valencia CA, Zhang K, Hostetter MK, Harley JB, Kaufman KM (2014) The struggle to find reliable results in exome sequencing data: filtering out Mendelian errors. Front Genet 5:16. PubMedPubMedCentralCrossRefGoogle Scholar
  23. 23.
    Namjou B, Marsolo K, Caroll RJ, Denny JC, Ritchie MD, Verma SS, Lingren T, Porollo A, Cobb BL, Perry C, Kottyan LC, Rothenberg ME, Thompson SD, Holm IA, Kohane IS, Harley JB (2014) Phenome-wide association study (PheWAS) in EMR-linked pediatric cohorts, genetically links PLCL1 to speech language development and IL5-IL13 to eosinophilic esophagitis. Front Genet 5:401. PubMedPubMedCentralCrossRefGoogle Scholar
  24. 24.
    Straumann A, Blanchard C, Radonjic-Hoesli S, Bussmann C, Hruz P, Safroneeva E, Simon D, Schoepfer AM, Simon HU (2016) A new eosinophilic esophagitis (EoE)-like disease without tissue eosinophilia found in EoE families. Allergy 71(6):889–900. PubMedCrossRefGoogle Scholar
  25. 25.
    Alexander ES, Martin LJ, Collins MH, Kottyan LC, Sucharew H, He H, Mukkada VA, Succop PA, Abonia JP, Foote H, Eby MD, Grotjan TM, Greenler AJ, Dellon ES, Demain JG, Furuta GT, Gurian LE, Harley JB, Hopp RJ, Kagalwalla A, Kaul A, Nadeau KC, Noel RJ, Putnam PE, von Tiehl KF, Rothenberg ME (2014) Twin and family studies reveal strong environmental and weaker genetic cues explaining heritability of eosinophilic esophagitis. J Allergy Clin Immunol 134(5):1084–1092.e1081. PubMedPubMedCentralCrossRefGoogle Scholar
  26. 26.
    Rothenberg ME (2015) Molecular, genetic, and cellular bases for treating eosinophilic esophagitis. Gastroenterology 148(6):1143–1157. PubMedPubMedCentralCrossRefGoogle Scholar
  27. 27.
    Zangwill SD, Brown MD, Bryke CR, Cava JR, Segura AD (2006) Marfan syndrome type II: there is more to Marfan syndrome than fibrillin 1. Congenit Heart Dis 1(5):229–232. PubMedCrossRefGoogle Scholar
  28. 28.
    Morissette R, Schoenhoff F, Xu Z, Shilane DA, Griswold BF, Chen W, Yang J, Zhu J, Fert-Bober J, Sloper L, Lehman J, Commins N, Van Eyk JE, McDonnell NB (2014) Transforming growth factor-beta and inflammation in vascular (type IV) Ehlers-Danlos syndrome. Circ Cardiovasc Genet 7(1):80–88. PubMedCrossRefGoogle Scholar
  29. 29.
    Samuelov L, Sarig O, Harmon RM, Rapaport D, Ishida-Yamamoto A, Isakov O, Koetsier JL, Gat A, Goldberg I, Bergman R, Spiegel R, Eytan O, Geller S, Peleg S, Shomron N, Goh CSM, Wilson NJ, Smith FJD, Pohler E, Simpson MA, McLean WHI, Irvine AD, Horowitz M, McGrath JA, Green KJ, Sprecher E (2013) Desmoglein 1 deficiency results in severe dermatitis, multiple allergies and metabolic wasting. Nat Genet 45(10):1244–1248. PubMedPubMedCentralCrossRefGoogle Scholar
  30. 30.
    Has C, Jakob T, He Y, Kiritsi D, Hausser I, Bruckner-Tuderman L (2014) Loss of desmoglein 1 associated with palmoplantar keratoderma, dermatitis and multiple allergies. Br J Dermatol 172(1):257–261. PubMedCrossRefGoogle Scholar
  31. 31.
    Sherrill JD, Kc K, Wu D, Djukic Z, Caldwell JM, Stucke EM, Kemme KA, Costello MS, Mingler MK, Blanchard C, Collins MH, Abonia JP, Putnam PE, Dellon ES, Orlando RC, Hogan SP, Rothenberg ME (2013) Desmoglein-1 regulates esophageal epithelial barrier function and immune responses in eosinophilic esophagitis. Mucosal Immunol 7(3):718–729. PubMedPubMedCentralCrossRefGoogle Scholar
  32. 32.
    Lyons JJ, Sun G, Stone KD, Nelson C, Wisch L, O'Brien M, Jones N, Lindsley A, Komarow HD, Bai Y, Scott LM, Cantave D, Maric I, Abonia JP, Rothenberg ME, Schwartz LB, Milner JD, Wilson TM (2014) Mendelian inheritance of elevated serum tryptase associated with atopy and connective tissue abnormalities. J Allergy Clin Immunol 133(5):1471–1474. PubMedPubMedCentralCrossRefGoogle Scholar
  33. 33.
    Johnson JB, Boynton KK, Peterson KA (2016) Co-occurrence of eosinophilic esophagitis and potential/probable celiac disease in an adult cohort: a possible association with implications for clinical practice. Dis Esophagus 29(8):977–982. PubMedCrossRefGoogle Scholar
  34. 34.
    Dharmaraj R, Hagglund K, Lyons H (2015) Eosinophilic esophagitis associated with celiac disease in children. BMC Res Notes 8(1):263. PubMedPubMedCentralCrossRefGoogle Scholar
  35. 35.
    Jensen ET, Eluri S, Lebwohl B, Genta RM, Dellon ES (2015) Increased risk of esophageal eosinophilia and eosinophilic esophagitis in patients with active celiac disease on biopsy. Clin Gastroenterol Hepatol 13(8):1426–1431. PubMedPubMedCentralCrossRefGoogle Scholar
  36. 36.
    Pellicano R, De Angelis C, Ribaldone DG, Fagoonee S, Astegiano M (2013) 2013 update on celiac disease and eosinophilic esophagitis. Nutrients 5(9):3329–3336. PubMedPubMedCentralCrossRefGoogle Scholar
  37. 37.
    Stewart MJ, Shaffer E, Urbanski SJ, Beck PL, Storr MA (2013) The association between celiac disease and eosinophilic esophagitis in children and adults. BMC Gastroenterol 13(1):96. PubMedPubMedCentralCrossRefGoogle Scholar
  38. 38.
    Le Fevre AK, Walker MM, Hadjiashrafy A, Bhatia R, Mattes J, Talley NJ, Nightingale S (2016) Elevated serum tissue transglutaminase antibodies in children with eosinophilic esophagitis. J Pediatr Gastroenterol Nutr 65(1):69–74. CrossRefGoogle Scholar
  39. 39.
    Cianferoni A, Spergel J (2016) Eosinophilic esophagitis: a comprehensive review. Clin Rev Allergy Immunol 50(2):159–174. PubMedCrossRefGoogle Scholar
  40. 40.
    Jensen ET, Hoffman K, Shaheen NJ, Genta RM, Dellon ES (2014) Esophageal eosinophilia is increased in rural areas with low population density: results from a national pathology database. Am J Gastroenterol 109(5):668–675. PubMedPubMedCentralCrossRefGoogle Scholar
  41. 41.
    Elitsur Y, Aswani R, Lund V, Dementieva Y (2013) Seasonal distribution and eosinophilic esophagitis: the experience in children living in rural communities. J Clin Gastroenterol 47(3):287–288. PubMedCrossRefGoogle Scholar
  42. 42.
    Spergel JM, Book WM, Mays E, Song L, Shah SS, Talley NJ, Bonis PA (2011) Variation in prevalence, diagnostic criteria, and initial management options for eosinophilic gastrointestinal diseases in the United States. J Pediatr Gastroenterol Nutr 52(3):300–306. PubMedPubMedCentralCrossRefGoogle Scholar
  43. 43.
    Hurrell JM, Genta RM, Dellon ES (2012) Prevalence of esophageal eosinophilia varies by climate zone in the United States. Am J Gastroenterol 107(5):698–706. PubMedPubMedCentralCrossRefGoogle Scholar
  44. 44.
    Stefka AT, Feehley T, Tripathi P, Qiu J, McCoy K, Mazmanian SK, Tjota MY, Seo GY, Cao S, Theriault BR, Antonopoulos DA, Zhou L, Chang EB, Fu YX, Nagler CR (2014) Commensal bacteria protect against food allergen sensitization. Proc Natl Acad Sci U S A 111(36):13145–13150. PubMedPubMedCentralCrossRefGoogle Scholar
  45. 45.
    Tsabouri S, Priftis KN, Chaliasos N, Siamopoulou A (2014) Modulation of gut microbiota downregulates the development of food allergy in infancy. Allergol Immunopathol (Madr) 42(1):69–77. CrossRefGoogle Scholar
  46. 46.
    Jensen ET, Kappelman MD, Kim HP, Ringel-Kulka T, Dellon ES (2013) Early life exposures as risk factors for pediatric eosinophilic esophagitis. J Pediatr Gastroenterol Nutr 57(1):67–71. PubMedCrossRefGoogle Scholar
  47. 47.
    Dellon ES, Chen X, Miller CR, Fritchie KJ, Rubinas TC, Woosley JT, Shaheen NJ (2011) Tryptase staining of mast cells may differentiate eosinophilic esophagitis from gastroesophageal reflux disease. Am J Gastroenterol 106(2):264–271. PubMedCrossRefGoogle Scholar
  48. 48.
    Rocha R, Vitor AB, Trindade E, Lima R, Tavares M, Lopes J, Dias JA (2011) Omalizumab in the treatment of eosinophilic esophagitis and food allergy. Eur J Pediatr 170(11):1471–1474. PubMedCrossRefGoogle Scholar
  49. 49.
    Mishra A, Schlotman J, Wang M, Rothenberg ME (2007) Critical role for adaptive T cell immunity in experimental eosinophilic esophagitis in mice. J Leukoc Biol 81(4):916–924. PubMedCrossRefGoogle Scholar
  50. 50.
    Gonsalves N, Yang GY, Doerfler B, Ritz S, Ditto AM, Hirano I (2012) Elimination diet effectively treats eosinophilic esophagitis in adults; food reintroduction identifies causative factors. Gastroenterology 142(7):1451–1459 e1451; quiz e1414-1455. PubMedCrossRefGoogle Scholar
  51. 51.
    Uzzaman A, Cho SH (2012) Chapter 28: classification of hypersensitivity reactions. Allergy Asthma Proc 33(3):96–99. PubMedCrossRefGoogle Scholar
  52. 52.
    Rayapudi M, Mavi P, Zhu X, Pandey AK, Abonia JP, Rothenberg ME, Mishra A (2010) Indoor insect allergens are potent inducers of experimental eosinophilic esophagitis in mice. J Leukoc Biol 88(2):337–346. PubMedPubMedCentralCrossRefGoogle Scholar
  53. 53.
    Pope SM, Fulkerson PC, Blanchard C, Akei HS, Nikolaidis NM, Zimmermann N, Molkentin JD, Rothenberg ME (2005) Identification of a cooperative mechanism involving interleukin-13 and eotaxin-2 in experimental allergic lung inflammation. J Biol Chem 280(14):13952–13961. PubMedCrossRefGoogle Scholar
  54. 54.
    Noti M, Wojno ED, Kim BS, Siracusa MC, Giacomin PR, Nair MG, Benitez AJ, Ruymann KR, Muir AB, Hill DA, Chikwava KR, Moghaddam AE, Sattentau QJ, Alex A, Zhou C, Yearley JH, Menard-Katcher P, Kubo M, Obata-Ninomiya K, Karasuyama H, Comeau MR, Brown-Whitehorn T, de Waal Malefyt R, Sleiman PM, Hakonarson H, Cianferoni A, Falk GW, Wang ML, Spergel JM, Artis D (2013) Thymic stromal lymphopoietin-elicited basophil responses promote eosinophilic esophagitis. Nat Med 19(8):1005–1013. PubMedPubMedCentralCrossRefGoogle Scholar
  55. 55.
    Akei HS, Brandt EB, Mishra A, Strait RT, Finkelman FD, Warrier MR, Khurana Hershey GK, Blanchard C, Rothenberg ME (2006) Epicutaneous aeroallergen exposure induces systemic TH2 immunity that predisposes to allergic nasal responses. J Allergy Clin Immunol 118(1):62–69. PubMedCrossRefGoogle Scholar
  56. 56.
    Spergel JM (2007) Eosinophilic esophagitis in adults and children: evidence for a food allergy component in many patients. Curr Opin Allergy Clin Immunol 7(3):274–278. PubMedCrossRefGoogle Scholar
  57. 57.
    Assa'ad AH, Putnam PE, Collins MH, Akers RM, Jameson SC, Kirby CL, Buckmeier BK, Bullock JZ, Collier AR, Konikoff MR, Noel RJ, Guajardo JR, Rothenberg ME (2007) Pediatric patients with eosinophilic esophagitis: an 8-year follow-up. J Allergy Clin Immunol 119(3):731–738. PubMedCrossRefGoogle Scholar
  58. 58.
    Spergel JM, Andrews T, Brown-Whitehorn TF, Beausoleil JL, Liacouras CA (2005) Treatment of eosinophilic esophagitis with specific food elimination diet directed by a combination of skin prick and patch tests. Ann Allergy Asthma Immunol 95(4):336–343. PubMedCrossRefGoogle Scholar
  59. 59.
    Liacouras CA, Spergel JM, Ruchelli E, Verma R, Mascarenhas M, Semeao E, Flick J, Kelly J, Brown-Whitehorn T, Mamula P, Markowitz JE (2005) Eosinophilic esophagitis: a 10-year experience in 381 children. Clin Gastroenterol Hepatol 3(12):1198–1206. PubMedCrossRefGoogle Scholar
  60. 60.
    Spergel JM, Beausoleil JL, Mascarenhas M, Liacouras CA (2002) The use of skin prick tests and patch tests to identify causative foods in eosinophilic esophagitis. J Allergy Clin Immunol 109(2):363–368. PubMedCrossRefGoogle Scholar
  61. 61.
    Simon D, Straumann A, Dahinden C, Simon HU (2013) Frequent sensitization to Candida albicans and profilins in adult eosinophilic esophagitis. Allergy 68(7):945–948. PubMedCrossRefGoogle Scholar
  62. 62.
    Spergel JM, Brown-Whitehorn TF, Cianferoni A, Shuker M, Wang ML, Verma R, Liacouras CA (2012) Identification of causative foods in children with eosinophilic esophagitis treated with an elimination diet. J Allergy Clin Immunol 130(2):461–467 e465 PubMedCrossRefGoogle Scholar
  63. 63.
    Henderson CJ, Abonia JP, King EC, Putnam PE, Collins MH, Franciosi JP, Rothenberg ME (2012) Comparative dietary therapy effectiveness in remission of pediatric eosinophilic esophagitis. J Allergy Clin Immunol 129(6):1570–1578. PubMedPubMedCentralCrossRefGoogle Scholar
  64. 64.
    van Rhijn BD, Vlieg-Boerstra BJ, Versteeg SA, Akkerdaas JH, van Ree R, Terreehorst I, Sprikkelman AB, Verheij J, Smout AJ, Bredenoord AJ (2015) Evaluation of allergen-microarray-guided dietary intervention as treatment of eosinophilic esophagitis. J Allergy Clin Immunol 136(4):1095–1097 e1093. PubMedCrossRefGoogle Scholar
  65. 65.
    Mondoulet L, Dioszeghy V, Puteaux E, Ligouis M, Dhelft V, Plaquet C, Dupont C, Benhamou PH (2015) Specific epicutaneous immunotherapy prevents sensitization to new allergens in a murine model. J Allergy Clin Immunol 135(6):1546–1557 e1544. PubMedCrossRefGoogle Scholar
  66. 66.
    Mondoulet L, Kalach N, Dhelft V, Larcher T, Delayre-Orthez C, Sampson HA, Benhamou P-H, Dupont CM Treatment of eosinophilic gastritis by epicutaneous immunotherapy (EPIT) in peanut allergic piglets. J Allergy Clin Immunol 139(2):AB48.
  67. 67.
    Chehade M, Aceves SS (2010) Food allergy and eosinophilic esophagitis. Curr Opin Allergy Clin Immunol 10(3):231–237. PubMedCrossRefGoogle Scholar
  68. 68.
    Maggadottir SM, Hill DA, Ruymann K, Brown-Whitehorn TF, Cianferoni A, Shuker M, Wang ML, Chikwava K, Verma R, Liacouras CA, Spergel JM (2014) Resolution of acute IgE-mediated allergy with development of eosinophilic esophagitis triggered by the same food. J Allergy Clin Immunol 133(5):1487–1489, e1481. PubMedCrossRefGoogle Scholar
  69. 69.
    Ho H-e, Chehade M Development of IgE-mediated immediate hypersensitivity to a previously tolerated food following its avoidance for eosinophilic gastrointestinal diseases (EGID): a case series. J Allergy Clin Immunol 139(2):AB53.
  70. 70.
    Lucendo AJ, Arias Á, Tenias JM (2014) Relation between eosinophilic esophagitis and oral immunotherapy for food allergy: a systematic review with meta-analysis. Ann Allergy Asthma Immunol 113(6):624–629. PubMedCrossRefGoogle Scholar
  71. 71.
    Ridolo E, De Angelis GL, Dall'aglio P (2011) Eosinophilic esophagitis after specific oral tolerance induction for egg protein. AnnAllergy Asthma Immunol 106(1):73–74. CrossRefGoogle Scholar
  72. 72.
    Miehlke S, Alpan O, Schroder S, Straumann A (2013) Induction of eosinophilic esophagitis by sublingual pollen immunotherapy. Case Rep Gastroenterol 7(3):363–368. PubMedPubMedCentralCrossRefGoogle Scholar
  73. 73.
    Babaie D, Mesdaghi M, Nishino M, Mansouri M, Ebisawa M (2017) Oral and sublingual immunotherapy: potential causes for eosinophilic gastrointestinal disorders? Int Arch Allergy Immunol 172(2):89–98. PubMedCrossRefGoogle Scholar
  74. 74.
    Clayton F, Fang JC, Gleich GJ, Lucendo AJ, Olalla JM, Vinson LA, Lowichik A, Chen X, Emerson L, Cox K, O'Gorman MA, Peterson KA (2014) Eosinophilic esophagitis in adults is associated with IgG4 and not mediated by IgE. Gastroenterology 147(3):602–609. PubMedCrossRefGoogle Scholar
  75. 75.
    Wright BL, Kulis M, Guo R, Orgel KA, Wolf WA, Burks AW, Vickery BP, Dellon ES (2016) Food-specific IgG4 is associated with eosinophilic esophagitis. J Allergy Clin Immunol 138(4):1190–1192.e1193. PubMedPubMedCentralCrossRefGoogle Scholar
  76. 76.
    Fogg MI, Ruchelli E, Spergel JM (2003) Pollen and eosinophilic esophagitis. J Allergy Clin Immunol 112(4):796–797. PubMedCrossRefGoogle Scholar
  77. 77.
    Moawad FJ, Veerappan GR, Lake JM, Maydonovitch CL, Haymore BR, Kosisky SE, Wong RK (2010) Correlation between eosinophilic oesophagitis and aeroallergens. Aliment Pharmacol Ther 31(4):509–515. PubMedCrossRefGoogle Scholar
  78. 78.
    Wolf WA, Jerath MR, Dellon ES (2013) De-novo onset of eosinophilic esophagitis after large volume allergen exposures. J Gastrointestin Liver Dis 22(2):205–208PubMedPubMedCentralGoogle Scholar
  79. 79.
    Mishra A, Rothenberg ME (2003) Intratracheal interleukin-13 induces eosinophilic esophagitis (EE). J Allergy Clin Immunol 111(2):S278. CrossRefGoogle Scholar
  80. 80.
    Mishra A, Hogan SP, Brandt EB, Rothenberg ME (2001) An etiological role for aeroallergens and eosinophils in experimental esophagitis. J Clin Invest 107(1):83–90. PubMedPubMedCentralCrossRefGoogle Scholar
  81. 81.
    Dellon ES, Gibbs WB, Fritchie KJ, Rubinas TC, Wilson LA, Woosley JT, Shaheen NJ (2009) Clinical, endoscopic, and histologic findings distinguish eosinophilic esophagitis from gastroesophageal reflux disease. Clin Gastroenterol Hepatol 7(12):1305–1313; quiz 1261. PubMedPubMedCentralCrossRefGoogle Scholar
  82. 82.
    Prasad GA, Alexander JA, Schleck CD, Zinsmeister AR, Smyrk TC, Elias RM, Locke GR, Talley NJ (2009) Epidemiology of eosinophilic esophagitis over three decades in Olmsted County, Minnesota. Clin Gastroenterol Hepatol 7(10):1055–1061. PubMedPubMedCentralCrossRefGoogle Scholar
  83. 83.
    Dellon ES (2014) Epidemiology of eosinophilic esophagitis. Gastroenterol Clin N Am 43(2):201–218. CrossRefGoogle Scholar
  84. 84.
    Almansa C, Krishna M, Buchner AM, Ghabril MS, Talley N, DeVault KR, Wolfsen H, Raimondo M, Guarderas JC, Achem SR (2009) Seasonal distribution in newly diagnosed cases of eosinophilic esophagitis in adults. Am J Gastroenterol 104(4):828–833. PubMedCrossRefGoogle Scholar
  85. 85.
    Wang FY, Gupta SK, Fitzgerald JF (2007) Is there a seasonal variation in the incidence or intensity of allergic eosinophilic esophagitis in newly diagnosed children? J Clin Gastroenterol 41(5):451–453. PubMedCrossRefGoogle Scholar
  86. 86.
    Larsson H, Bergquist H, Bove M (2011) The incidence of esophageal bolus impaction: is there a seasonal variation? Otolaryngol Head Neck Surg 144(2):186–190. PubMedCrossRefGoogle Scholar
  87. 87.
    Bene J, Ley D, Roboubi R, Gottrand F, Gautier S (2016) Eosinophilic esophagitis after desensitization to dust mites with sublingual immunotherapy. Ann Allergy Asthma Immunol 116(6):583–584. PubMedCrossRefGoogle Scholar
  88. 88.
    Simon D, Marti H, Heer P, Simon HU, Braathen LR, Straumann A (2005) Eosinophilic esophagitis is frequently associated with IgE-mediated allergic airway diseases. J Allergy Clin Immunol 115(5):1090–1092. PubMedCrossRefGoogle Scholar
  89. 89.
    van Rhijn BD, van Ree R, Versteeg SA, Vlieg-Boerstra BJ, Sprikkelman AB, Terreehorst I, Smout AJPM, Bredenoord AJ (2013) Birch pollen sensitization with cross-reactivity to food allergens predominates in adults with eosinophilic esophagitis. Allergy 68(11):1475–1481. PubMedCrossRefGoogle Scholar
  90. 90.
    de Fraissinette A, Schmitt D, Thivolet J (1989) Langerhans cells of human mucosa. J Dermatol 16(4):255–262. PubMedCrossRefGoogle Scholar
  91. 91.
    Lopez-Torrejon G, Crespo JF, Sanchez-Monge R, Sanchez-Jimenez M, Alvarez J, Rodriguez J, Salcedo G (2005) Allergenic reactivity of the melon profilin Cuc m 2 and its identification as major allergen. Clin Exp Allergy 35(8):1065–1072. PubMedCrossRefGoogle Scholar
  92. 92.
    Padia R, Curtin K, Peterson K, Orlandi RR, Alt J (2016) Eosinophilic esophagitis strongly linked to chronic rhinosinusitis. Laryngoscope 126(6):1279–1283. PubMedCrossRefGoogle Scholar
  93. 93.
    Akdis CA, Akdis M, Simon D, Dibbert B, Weber M, Gratzl S, Kreyden O, Disch R, Wuthrich B, Blaser K, Simon HU (1999) T cells and T cell-derived cytokines as pathogenic factors in the nonallergic form of atopic dermatitis. J Invest Dermatol 113(4):628–634. PubMedCrossRefGoogle Scholar
  94. 94.
    Breuer K, Heratizadeh A, Wulf A, Baumann U, Constien A, Tetau D, Kapp A, Werfel T (2004) Late eczematous reactions to food in children with atopic dermatitis. Clin Exp Allergy 34(5):817–824. PubMedCrossRefGoogle Scholar
  95. 95.
    Reekers R, Beyer K, Niggemann B, Wahn U, Freihorst J, Kapp A, Werfel T (1996) The role of circulating food antigen-specific lymphocytes in food allergic children with atopic dermatitis. Br J Dermatol 135(6):935–941. PubMedCrossRefGoogle Scholar
  96. 96.
    Reekers R, Busche M, Wittmann M, Kapp A, Werfel T (1999) Birch pollen-related foods trigger atopic dermatitis in patients with specific cutaneous T-cell responses to birch pollen antigens. J Allergy Clin Immunol 104(2 Pt 1):466–472. PubMedCrossRefGoogle Scholar
  97. 97.
    Darsow U, Laifaoui J, Kerschenlohr K, Wollenberg A, Przybilla B, Wuthrich B, Borelli S Jr, Giusti F, Seidenari S, Drzimalla K, Simon D, Disch R, Borelli S, Devillers AC, Oranje AP, De Raeve L, Hachem JP, Dangoisse C, Blondeel A, Song M, Breuer K, Wulf A, Werfel T, Roul S, Taieb A, Bolhaar S, Bruijnzeel-Koomen C, Bronnimann M, Braathen LR, Didierlaurent A, Andre C, Ring J (2004) The prevalence of positive reactions in the atopy patch test with aeroallergens and food allergens in subjects with atopic eczema: a European multicenter study. Allergy 59(12):1318–1325. PubMedCrossRefGoogle Scholar
  98. 98.
    Rothenberg ME, Wen T, Greenberg A, Alpan O, Enav B, Hirano I, Nadeau K, Kaiser S, Peters T, Perez A, Jones I, Arm JP, Strieter RM, Sabo R, Gunawardena KA (2015) Intravenous anti-IL-13 mAb QAX576 for the treatment of eosinophilic esophagitis. J Allergy Clin Immunol 135(2):500–507. PubMedCrossRefGoogle Scholar
  99. 99.
    Assa'ad AH, Gupta SK, Collins MH, Thomson M, Heath AT, Smith DA, Perschy TL, Jurgensen CH, Ortega HG, Aceves SS (2011) An antibody against IL-5 reduces numbers of esophageal intraepithelial eosinophils in children with eosinophilic esophagitis. Gastroenterology 141(5):1593–1604. PubMedCrossRefGoogle Scholar
  100. 100.
    Kottyan LC, Rothenberg ME (2017) Genetics of eosinophilic esophagitis. Mucosal Immunol 10(3):580–588. PubMedPubMedCentralCrossRefGoogle Scholar
  101. 101.
    Corridoni D, Arseneau KO, Cominelli F (2014) Inflammatory bowel disease. Immunol Lett 161(2):231–235. PubMedPubMedCentralCrossRefGoogle Scholar
  102. 102.
    Xavier RJ, Podolsky DK (2007) Unravelling the pathogenesis of inflammatory bowel disease. Nature 448(7152):427–434. PubMedCrossRefGoogle Scholar
  103. 103.
    Mavi P, Rajavelu P, Rayapudi M, Paul RJ, Mishra A (2012) Esophageal functional impairments in experimental eosinophilic esophagitis. AJP Gastrointestin Liver Physiol 302(11):G1347–G1355. CrossRefGoogle Scholar
  104. 104.
    Mishra A, Wang M, Pemmaraju VR, Collins MH, Fulkerson PC, Abonia JP, Blanchard C, Putnam PE, Rothenberg ME (2008) Esophageal remodeling develops as a consequence of tissue specific IL-5-induced eosinophilia. Gastroenterology 134(1):204–214. PubMedCrossRefGoogle Scholar
  105. 105.
    Rubinstein E, Cho JY, Rosenthal P, Chao J, Miller M, Pham A, Aceves SS, Varki A, Broide DH (2011) Siglec-F inhibition reduces esophageal eosinophilia and angiogenesis in a mouse model of eosinophilic esophagitis. J Pediatr Gastroenterol Nutr 53(4):409–416. PubMedPubMedCentralCrossRefGoogle Scholar
  106. 106.
    Davis BP, Rothenberg ME (2013) Antigen presentation by eosinophils in eosinophilic esophagitis? J Pediatr Gastroenterol Nutr 56(3):242. PubMedCrossRefGoogle Scholar
  107. 107.
    Abonia JP, Blanchard C, Butz BB, Rainey HF, Collins MH, Stringer K, Putnam PE, Rothenberg ME (2010) Involvement of mast cells in eosinophilic esophagitis. J Allergy Clin Immunol 126(1):140–149. PubMedPubMedCentralCrossRefGoogle Scholar
  108. 108.
    Aceves SS, Chen D, Newbury RO, Dohil R, Bastian JF, Broide DH (2010) Mast cells infiltrate the esophageal smooth muscle in patients with eosinophilic esophagitis, express TGF-β1, and increase esophageal smooth muscle contraction. J Allergy Clin Immunol 126(6):1198–1204.e1194. PubMedCrossRefGoogle Scholar
  109. 109.
    Straumann A, H-p S, Grize L, Bucher KA, Beglinger C, H-u S (2003) Natural history of primary eosinophilic esophagitis: a follow-up of 30 adult patients for up to 11.5 years. Gastroenterology 125(6):1660–1669. PubMedCrossRefGoogle Scholar
  110. 110.
    Chehade M, Sampson HA, Morotti RA, Magid MS (2007) Esophageal subepithelial fibrosis in children with eosinophilic esophagitis. J Pediatr Gastroenterol Nutr 45(3):319–328. PubMedCrossRefGoogle Scholar
  111. 111.
    Aceves SS, Newbury RO, Dohil R, Bastian JF, Broide DH (2007) Esophageal remodeling in pediatric eosinophilic esophagitis. J Allergy Clin Immunol 119(1):206–212. PubMedCrossRefGoogle Scholar
  112. 112.
    Bara I, Ozier A, Tunon de Lara JM, Marthan R, Berger P (2010) Pathophysiology of bronchial smooth muscle remodelling in asthma. Eur Respir J 36(5):1174–1184. PubMedCrossRefGoogle Scholar
  113. 113.
    Van Nassauw L, Adriaensen D, Timmermans J-P (2007) The bidirectional communication between neurons and mast cells within the gastrointestinal tract. Auton Neurosci 133(1):91–103. PubMedCrossRefGoogle Scholar
  114. 114.
    Niranjan R, Mavi P, Rayapudi M, Dynda S, Mishra A (2013) Pathogenic role of mast cells in experimental eosinophilic esophagitis. AJP Gastrointestin Liver Physiol 304(12):G1087–G1094. CrossRefGoogle Scholar
  115. 115.
    Otani IM, Anilkumar AA, Newbury RO, Bhagat M, Beppu LY, Dohil R, Broide DH, Aceves SS (2013) Anti–IL-5 therapy reduces mast cell and IL-9 cell numbers in pediatric patients with eosinophilic esophagitis. J Allergy Clin Immunol 131(6):1576–1582.e1572. PubMedPubMedCentralCrossRefGoogle Scholar
  116. 116.
    Blanchard C, Stucke EM, Rodriguez-Jimenez B, Burwinkel K, Collins MH, Ahrens A, Alexander ES, Buckmeier Butz BK, Jameson SC, Kaul A (2011) A striking local esophageal cytokine expression profile in eosinophilic esophagitis. J Allergy Clin Immunol 127(1):208–217.e207. PubMedPubMedCentralCrossRefGoogle Scholar
  117. 117.
    Goswami R, Kaplan MH (2011) A brief history of IL-9. J Immunol 186(6):3283–3288. PubMedPubMedCentralCrossRefGoogle Scholar
  118. 118.
    Siracusa MC, Saenz SA, Hill DA, Kim BS, Headley MB, Doering TA, Wherry EJ, Jessup HK, Siegel LA, Kambayashi T, Dudek EC, Kubo M, Cianferoni A, Spergel JM, Ziegler SF, Comeau MR, Artis D (2011) TSLP promotes interleukin-3-independent basophil haematopoiesis and type 2 inflammation. Nature 477(7363):229–233. PubMedPubMedCentralCrossRefGoogle Scholar
  119. 119.
    Mulder DJ, Pooni A, Mak N, Hurlbut DJ, Basta S, Justinich CJ (2011) Antigen presentation and MHC class II expression by human esophageal epithelial cells. Am J Pathol 178(2):744–753. PubMedPubMedCentralCrossRefGoogle Scholar
  120. 120.
    Straumann A, Bauer M, Fischer B, Blaser K, Simon H-U (2001) Idiopathic eosinophilic esophagitis is associated with a TH2-type allergic inflammatory response. J Allergy Clin Immunol 108(6):954–961. PubMedCrossRefGoogle Scholar
  121. 121.
    Tantibhaedhyangkul U, Tatevian N, Gilger MA, Major AM, Davis CM (2009) Increased esophageal regulatory T cells and eosinophil characteristics in children with eosinophilic esophagitis and gastroesophageal reflux disease. Ann Clin Lab Sci 39(2):99–107PubMedGoogle Scholar
  122. 122.
    Kool M, Willart Monique AM, van Nimwegen M, Bergen I, Pouliot P, Virchow JC, Rogers N, Osorio F, Reis e Sousa C, Hammad H, Lambrecht Bart N (2011) An unexpected role for uric acid as an inducer of T helper 2 cell immunity to inhaled antigens and inflammatory mediator of allergic asthma. Immunity 34(4):527–540. PubMedCrossRefGoogle Scholar
  123. 123.
    Hammad H, Chieppa M, Perros F, Willart MA, Germain RN, Lambrecht BN (2009) House dust mite allergen induces asthma via Toll-like receptor 4 triggering of airway structural cells. Nat Med 15(4):410–416. PubMedPubMedCentralCrossRefGoogle Scholar
  124. 124.
    Eiwegger T, Akdis CA (2011) IL-33 links tissue cells, dendritic cells and Th2 cell development in a mouse model of asthma. Eur J Immunol 41(6):1535–1538. PubMedCrossRefGoogle Scholar
  125. 125.
    Teitelbaum JE, Fox VL, Twarog FJ, Nurko S, Antonioli D, Gleich G, Badizadegan K, Furuta GT (2002) Eosinophilic esophagitis in children: immunopathological analysis and response to fluticasone propionate. Gastroenterology 122(5):1216–1225. PubMedCrossRefGoogle Scholar
  126. 126.
    Lucendo AJ, Navarro M, Comas C, Pascual JM, Burgos E, Santamaria L, Larrauri J (2007) Immunophenotypic characterization and quantification of the epithelial inflammatory infiltrate in eosinophilic esophagitis through stereology. Am J Surg Pathol 31(4):598–606. PubMedCrossRefGoogle Scholar
  127. 127.
    Blanchard C, Mingler MK, Vicario M, Abonia JP, Wu YY, Lu TX, Collins MH, Putnam PE, Wells SI, Rothenberg ME (2007) IL-13 involvement in eosinophilic esophagitis: transcriptome analysis and reversibility with glucocorticoids. J Allergy Clin Immunol 120(6):1292–1300. PubMedCrossRefGoogle Scholar
  128. 128.
    Vicario M, Blanchard C, Stringer KF, Collins MH, Mingler MK, Ahrens A, Putnam PE, Abonia JP, Santos J, Rothenberg ME (2009) Local B cells and IgE production in the oesophageal mucosa in eosinophilic oesophagitis. Gut 59(01):12–20. PubMedCentralCrossRefGoogle Scholar
  129. 129.
    Stuck MC, Straumann A, Simon HU (2010) Relative lack of T regulatory cells in adult eosinophilic esophagitis—no normalization after corticosteroid therapy. Allergy 66(5):705–707. PubMedCrossRefGoogle Scholar
  130. 130.
    Jyonouchi S, Smith CL, Saretta F, Abraham V, Ruymann KR, Modayur-Chandramouleeswaran P, Wang ML, Spergel JM, Cianferoni A (2013) Invariant natural killer T cells in children with eosinophilic esophagitis. Clin Exp Allergy 44(1):58–68. CrossRefGoogle Scholar
  131. 131.
    Rayapudi M, Rajavelu P, Zhu X, Kaul A, Niranjan R, Dynda S, Mishra A, Mattner J, Zaidi A, Dutt P, Mishra A (2014) Invariant natural killer T-cell neutralization is a possible novel therapy for human eosinophilic esophagitis. Clin Transl Immunol 3(1):e9. CrossRefGoogle Scholar
  132. 132.
    Montalvillo E, Garrote JA, Bernardo D, Arranz E (2014) Innate lymphoid cells and natural killer T cells in the gastrointestinal tract immune system. Rev Esp Enferm Dig 106(5):334–345PubMedGoogle Scholar
  133. 133.
    Berin MC, Shreffler WG (2008) TH2 adjuvants: implications for food allergy. J Allergy Clin Immunol 121(6):1311–1320. PubMedCrossRefGoogle Scholar
  134. 134.
    Rajavelu P, Rayapudi M, Moffitt M, Mishra A, Mishra A (2011) Significance of para-esophageal lymph nodes in food or aeroallergen-induced iNKT cell-mediated experimental eosinophilic esophagitis. AJP Gastrointestin Liver Physiol 302(7):G645–G654. CrossRefGoogle Scholar
  135. 135.
    Olszak T, An D, Zeissig S, Vera MP, Richter J, Franke A, Glickman JN, Siebert R, Baron RM, Kasper DL, Blumberg RS (2012) Microbial exposure during early life has persistent effects on natural killer T cell function. Science 336(6080):489–493. PubMedPubMedCentralCrossRefGoogle Scholar
  136. 136.
    Garn H, Renz H (2007) Epidemiological and immunological evidence for the hygiene hypothesis. Immunobiology 212(6):441–452. PubMedCrossRefGoogle Scholar
  137. 137.
    Lexmond WS, Neves JF, Nurko S, Olszak T, Exley MA, Blumberg RS, Fiebiger E (2014) Involvement of the iNKT cell pathway is associated with early-onset eosinophilic esophagitis and response to allergen avoidance therapy. Am J Gastroenterol 109(5):646–657. PubMedPubMedCentralCrossRefGoogle Scholar
  138. 138.
    Doherty TA, Baum R, Newbury RO, Yang T, Dohil R, Aquino M, Doshi A, Walford HH, Kurten RC, Broide DH, Aceves S (2015) Group 2 innate lymphocytes (ILC2) are enriched in active eosinophilic esophagitis. J Allergy Clin Immunol 136(3):792–794.e793. PubMedPubMedCentralCrossRefGoogle Scholar
  139. 139.
    Mjosberg JM, Trifari S, Crellin NK, Peters CP, van Drunen CM, Piet B, Fokkens WJ, Cupedo T, Spits H (2011) Human IL-25- and IL-33-responsive type 2 innate lymphoid cells are defined by expression of CRTH2 and CD161. Nat Immunol 12(11):1055–1062. PubMedCrossRefGoogle Scholar
  140. 140.
    Christianson CA, Goplen NP, Zafar I, Irvin C, Good JT Jr, Rollins DR, Gorentla B, Liu W, Gorska MM, Chu H, Martin RJ, Alam R (2015) Persistence of asthma requires multiple feedback circuits involving type 2 innate lymphoid cells and IL-33. J Allergy Clin Immunol 136(1):59–68.e14. PubMedPubMedCentralCrossRefGoogle Scholar
  141. 141.
    Akei HS, Mishra A, Blanchard C, Rothenberg ME (2005) Epicutaneous antigen exposure primes for experimental eosinophilic esophagitis in mice. Gastroenterology 129(3):985–994. PubMedCrossRefGoogle Scholar
  142. 142.
    Blanchard C, Rothenberg ME (2008) Basic pathogenesis of eosinophilic esophagitis. Gastrointest Endosc Clin N Am 18(1):133–143. PubMedPubMedCentralCrossRefGoogle Scholar
  143. 143.
    Lucendo AJ, De Rezende L, Comas C, Caballero T, Bellón T (2008) Treatment with topical steroids downregulates IL-5, Eotaxin-1/CCL11, and eotaxin-3/CCL26 gene expression in eosinophilic esophagitis. Am J Gastroenterol 103(9):2184–2193. PubMedCrossRefGoogle Scholar
  144. 144.
    Zhu X, Wang M, Mavi P, Rayapudi M, Pandey AK, Kaul A, Putnam PE, Rothenberg ME, Mishra A (2010) Interleukin-15 expression is increased in human eosinophilic esophagitis and mediates pathogenesis in mice. Gastroenterology 139(1):182–193.e187. PubMedPubMedCentralCrossRefGoogle Scholar
  145. 145.
    O'Byrne PM, Inman MD, Parameswaran K (2001) The trials and tribulations of IL-5, eosinophils, and allergic asthma. J Allergy Clin Immunol 108(4):503–508. PubMedCrossRefGoogle Scholar
  146. 146.
    Straumann A, Conus S, Grzonka P, Kita H, Kephart G, Bussmann C, Beglinger C, Smith DA, Patel J, Byrne M, Simon HU (2009) Anti-interleukin-5 antibody treatment (mepolizumab) in active eosinophilic oesophagitis: a randomised, placebo-controlled, double-blind trial. Gut 59(01):21–30. CrossRefGoogle Scholar
  147. 147.
    Yamazaki K, Murray JA, Arora AS, Alexander JA, Smyrk TC, Butterfield JH, Kita H (2006) Allergen-specific in vitro cytokine production in adult patients with eosinophilic esophagitis. Dig Dis Sci 51(11):1934–1941. PubMedCrossRefGoogle Scholar
  148. 148.
    Straumann A, Kristl J, Conus S, Vassina E, Spichtin H-P, Beglinger C, Simon H-U (2005) Cytokine expression in healthy and inflamed mucosa: probing the role of eosinophils in the digestive tract. Inflamm Bowel Dis 11(8):720–726. PubMedCrossRefGoogle Scholar
  149. 149.
    Zuo L, Fulkerson PC, Finkelman FD, Mingler M, Fischetti CA, Blanchard C, Rothenberg ME (2010) IL-13 induces esophageal remodeling and gene expression by an eosinophil-independent, IL-13R 2-inhibited pathway. J Immunol 185(1):660–669. PubMedPubMedCentralCrossRefGoogle Scholar
  150. 150.
    Blanchard C, Mishra A, Saito-Akei H, Monk P, Anderson I, Rothenberg ME (2005) Inhibition of human interleukin-13-induced respiratory and oesophageal inflammation by anti-human-interleukin-13 antibody (CAT-354). Clin Exp Allergy 35(8):1096–1103. PubMedCrossRefGoogle Scholar
  151. 151.
    Blanchard C, Mingler MK, McBride M, Putnam PE, Collins MH, Chang G, Stringer K, Abonia JP, Molkentin JD, Rothenberg ME (2008) Periostin facilitates eosinophil tissue infiltration in allergic lung and esophageal responses. Mucosal Immunol 1(4):289–296. PubMedPubMedCentralCrossRefGoogle Scholar
  152. 152.
    Sherrill JD, Kc K, Wu D, Djukic Z, Caldwell JM, Stucke EM, Kemme KA, Costello MS, Mingler MK, Blanchard C, Collins MH, Abonia JP, Putnam PE, Dellon ES, Orlando RC, Hogan SP, Rothenberg ME (2014) Desmoglein-1 regulates esophageal epithelial barrier function and immune responses in eosinophilic esophagitis. Mucosal Immunol 7(3):718–729. PubMedCrossRefGoogle Scholar
  153. 153.
    Cheng E, Zhang X, Wilson KS, Wang DH, Park JY, Huo X, Yu C, Zhang Q, Spechler SJ, Souza RF (2016) JAK-STAT6 pathway inhibitors block eotaxin-3 secretion by epithelial cells and fibroblasts from esophageal eosinophilia patients: promising agents to improve inflammation and prevent fibrosis in EoE. PLoS One 11(6):e0157376. PubMedPubMedCentralCrossRefGoogle Scholar
  154. 154.
    Straumann A, Conus S, Degen L, Felder S, Kummer M, Engel H, Bussmann C, Beglinger C, Schoepfer A, Simon HU (2010) Budesonide is effective in adolescent and adult patients with active eosinophilic esophagitis. Gastroenterology 139(5):1526–1537.e1521. PubMedCrossRefGoogle Scholar
  155. 155.
    Frischmeyer-Guerrerio PA, Guerrerio AL, Oswald G, Chichester K, Myers L, Halushka MK, Oliva-Hemker M, Wood RA, Dietz HC (2013) TGF receptor mutations impose a strong predisposition for human allergic disease. Sci Transl Med 5(195):195ra194–195ra194. CrossRefGoogle Scholar
  156. 156.
    Rawson R, Yang T, Newbury RO, Aquino M, Doshi A, Bell B, Broide DH, Dohil R, Kurten R, Aceves SS (2016) TGF-beta1-induced PAI-1 contributes to a profibrotic network in patients with eosinophilic esophagitis. J Allergy Clin Immunol 138(3):791–800.e794. PubMedPubMedCentralCrossRefGoogle Scholar
  157. 157.
    Rawson R, Anilkumar A, Newbury RO, Bafna V, Aquino M, Palmquist J, Hoffman HM, Mueller JL, Dohil R, Broide DH, Aceves SS (2015) The TGFbeta1 promoter SNP C-509T and food sensitization promote esophageal remodeling in pediatric eosinophilic esophagitis. PLoS One 10(12):e0144651. PubMedPubMedCentralCrossRefGoogle Scholar
  158. 158.
    Collison AM, Sokulsky LA, Sherrill JD, Nightingale S, Hatchwell L, Talley NJ, Walker MM, Rothenberg ME, Mattes J (2015) TNF-related apoptosis-inducing ligand (TRAIL) regulates midline-1, thymic stromal lymphopoietin, inflammation, and remodeling in experimental eosinophilic esophagitis. J Allergy Clin Immunol 136(4):971–982. PubMedPubMedCentralCrossRefGoogle Scholar
  159. 159.
    de Souza HS, Tortori CA, Lintomen L, Figueiredo RT, Bernardazzi C, Leng L, Bucala R, Madi K, Buongusto F, Elia CC, Castelo-Branco MT, Bozza MT (2015) Macrophage migration inhibitory factor promotes eosinophil accumulation and tissue remodeling in eosinophilic esophagitis. Mucosal Immunol 8(5):1154–1165. PubMedPubMedCentralCrossRefGoogle Scholar
  160. 160.
    Dutt P, Shukla JS, Ventateshaiah SU, Mariswamy SJ, Mattner J, Shukla A, Mishra A (2015) Allergen-induced interleukin-18 promotes experimental eosinophilic oesophagitis in mice. Immunol Cell Biol 93(10):849–857. PubMedPubMedCentralCrossRefGoogle Scholar
  161. 161.
    Zhang S, Wu X, Yu S (2013) Prostaglandin D2 receptord-type prostanoid receptor 2 mediates eosinophil trafficking into the esophagus. Dis Esophagus 27(6):601–606. PubMedPubMedCentralCrossRefGoogle Scholar
  162. 162.
    Pettipher R, Hansel TT, Armer R (2007) Antagonism of the prostaglandin D2 receptors DP1 and CRTH2 as an approach to treat allergic diseases. Nat Rev Drug Discov 6(4):313–325. PubMedCrossRefGoogle Scholar
  163. 163.
    Straumann A, Hoesli S, Bussmann C, Stuck M, Perkins M, Collins LP, Payton M, Pettipher R, Hunter M, Steiner J, Simon HU (2013) Anti-eosinophil activity and clinical efficacy of the CRTH2 antagonist OC000459 in eosinophilic esophagitis. Allergy 68(3):375–385. PubMedCrossRefGoogle Scholar
  164. 164.
    Takhar P, Corrigan CJ, Smurthwaite L, O'Connor BJ, Durham SR, Lee TH, Gould HJ (2007) Class switch recombination to IgE in the bronchial mucosa of atopic and nonatopic patients with asthma. J Allergy Clin Immunol 119(1):213–218. PubMedCrossRefGoogle Scholar
  165. 165.
    Takhar P, Smurthwaite L, Coker HA, Fear DJ, Banfield GK, Carr VA, Durham SR, Gould HJ (2005) Allergen drives class switching to IgE in the nasal mucosa in allergic rhinitis. J Immunol 174(8):5024–5032. PubMedCrossRefGoogle Scholar
  166. 166.
    Erwin EA, Kruszewski PG, Russo JM, Schuyler AJ, Platts-Mills TA (2016) IgE antibodies and response to cow’s milk elimination diet in pediatric eosinophilic esophagitis. J Allergy Clin Immunol 138(2):625–628.e622. PubMedPubMedCentralCrossRefGoogle Scholar
  167. 167.
    Schuyler AJ, Erwin EA, Oken E, Rifas-Shiman S, Lidholm J, Wilson J, Tripathi A, Workman LJ, Gold DR, Platts-Mills TAE The diagnostic utility of serum assays for total IgG4 and specific IgG4 antibodies to cow's milk proteins in children with eosinophilic esophagitis: comparison with an unselected birth cohort. J Allergy Clin Immunol 139(2):AB48.
  168. 168.
    Wilson J, Schuyler AJ, Tripathi A, Commins SP, Erwin EA, Platts-Mills TAE Serum IgG4 to food proteins, but not to the barrier function proteins desmoglein 1 or 3, are increased in eosinophilic esophagitis. J Allergy Clin Immunol 139(2):AB50.
  169. 169.
    Blanchard C (2015) Molecular pathogenesis of eosinophilic esophagitis. Curr Opin Gastroenterol 31(4):321–327. PubMedCrossRefGoogle Scholar
  170. 170.
    Sherrill JD, Kiran KC, Blanchard C, Stucke EM, Kemme KA, Collins MH, Abonia JP, Putnam PE, Mukkada VA, Kaul A, Kocoshis SA, Kushner JP, Plassard AJ, Karns RA, Dexheimer PJ, Aronow BJ, Rothenberg ME (2014) Analysis and expansion of the eosinophilic esophagitis transcriptome by RNA sequencing. Genes Immun 15(6):361–369. PubMedPubMedCentralCrossRefGoogle Scholar
  171. 171.
    Kc K, Rothenberg ME, Sherrill JD (2015) In vitro model for studying esophageal epithelial differentiation and allergic inflammatory responses identifies keratin involvement in eosinophilic esophagitis. PLoS One 10(6):e0127755. PubMedPubMedCentralCrossRefGoogle Scholar
  172. 172.
    Wen T, Stucke EM, Grotjan TM, Kemme KA, Abonia JP, Putnam PE, Franciosi JP, Garza JM, Kaul A, King EC, Collins MH, Kushner JP, Rothenberg ME (2013) Molecular diagnosis of eosinophilic esophagitis by gene expression profiling. Gastroenterology 145(6):1289–1299. PubMedPubMedCentralCrossRefGoogle Scholar
  173. 173.
    Wen T, Dellon ES, Moawad FJ, Furuta GT, Aceves SS, Rothenberg ME (2015) Transcriptome analysis of proton pump inhibitor-responsive esophageal eosinophilia reveals proton pump inhibitor–reversible allergic inflammation. J Allergy Clin Immunol 135(1):187–197.e184. PubMedCrossRefGoogle Scholar
  174. 174.
    Shoda T, Matsuda A, Nomura I, Okada N, Orihara K, Mikami H, Ishimura N, Ishihara S, Matsumoto K, Kinoshita Y (2017) Eosinophilic esophagitis versus proton pump inhibitor-responsive esophageal eosinophilia: transcriptome analysis. J Allergy Clin Immunol 139(6):2010–2013.e4. PubMedCrossRefGoogle Scholar
  175. 175.
    Behm-Ansmant I, Rehwinkel J, Izaurralde E (2006) MicroRNAs silence gene expression by repressing protein expression and/or by promoting mRNA decay. Cold Spring Harb Symp Quant Biol 71(0):523–530. PubMedCrossRefGoogle Scholar
  176. 176.
    Lu TX, Sherrill JD, Wen T, Plassard AJ, Besse JA, Abonia JP, Franciosi JP, Putnam PE, Eby M, Martin LJ, Aronow BJ, Rothenberg ME (2012) MicroRNA signature in patients with eosinophilic esophagitis, reversibility with glucocorticoids, and assessment as disease biomarkers. J Allergy Clin Immunol 129(4):1064–1075.e1069. PubMedPubMedCentralCrossRefGoogle Scholar
  177. 177.
    Lu S, Mukkada VA, Mangray S, Cleveland K, Shillingford N, Schorl C, Brodsky AS, Resnick MB (2012) MicroRNA profiling in mucosal biopsies of eosinophilic esophagitis patients pre and post treatment with steroids and relationship with mRNA targets. PLoS One 7(7):e40676. PubMedPubMedCentralCrossRefGoogle Scholar
  178. 178.
    Lu TX, Lim EJ, Wen T, Plassard AJ, Hogan SP, Martin LJ, Aronow BJ, Rothenberg ME (2012) MiR-375 is downregulated in epithelial cells after IL-13 stimulation and regulates an IL-13-induced epithelial transcriptome. Mucosal Immunol 5(4):388–396. PubMedPubMedCentralCrossRefGoogle Scholar
  179. 179.
    Odze RD (2009) Pathology of eosinophilic esophagitis: what the clinician needs to know. Am J Gastroenterol 104(2):485–490. PubMedCrossRefGoogle Scholar
  180. 180.
    Kubo A, Nagao K, Amagai M (2012) Epidermal barrier dysfunction and cutaneous sensitization in atopic diseases. J Clin Investig 122(2):440–447. PubMedCrossRefGoogle Scholar
  181. 181.
    Mueller S, Aigner T, Neureiter D, Stolte M (2006) Eosinophil infiltration and degranulation in oesophageal mucosa from adult patients with eosinophilic oesophagitis: a retrospective and comparative study on pathological biopsy. J Clin Pathol 59(11):1175–1180. PubMedPubMedCentralCrossRefGoogle Scholar
  182. 182.
    Ravelli AM, Villanacci V, Ruzzenenti N, Grigolato P, Tobanelli P, Klersy C, Rindi G (2006) Dilated intercellular spaces. J Pediatr Gastroenterol Nutr 42(5):510–515. PubMedCrossRefGoogle Scholar
  183. 183.
    Lucendo AJ, Lucendo B (2010) An update on the immunopathogenesis of eosinophilic esophagitis. Expert Rev Gastroenterol Hepatol 4(2):141–148. PubMedCrossRefGoogle Scholar
  184. 184.
    Rochman M, Travers J, Miracle CE, Bedard MC, Wen T, Azouz NP, Caldwell JM, Kc K, Sherrill JD, Davis BP, Rymer JK, Kaufman KM, Aronow BJ, Rothenberg ME (2017) Profound loss of esophageal tissue differentiation in patients with eosinophilic esophagitis. J Allergy Clin Immunol 140(3):738–749.e3. PubMedCrossRefPubMedCentralGoogle Scholar
  185. 185.
    South AP, Ives JH, James CH, Nizetic D, Cabral A, Mirza G, Marenholz I, Mischke D, Backendorf C, Ragoussis J (1999) Human epidermal differentiation complex in a single 2.5 Mbp long continuum of overlapping DNA cloned in bacteria integrating physical and transcript maps. J Investig Dermatol 112(6):910–918. PubMedCrossRefGoogle Scholar
  186. 186.
    Fallon PG, Sasaki T, Sandilands A, Campbell LE, Saunders SP, Mangan NE, Callanan JJ, Kawasaki H, Shiohama A, Kubo A, Sundberg JP, Presland RB, Fleckman P, Shimizu N, Kudoh J, Irvine AD, Amagai M, McLean WHI (2009) A homozygous frameshift mutation in the mouse Flg gene facilitates enhanced percutaneous allergen priming. Nat Genet 41(5):602–608. PubMedPubMedCentralCrossRefGoogle Scholar
  187. 187.
    O'Regan GM, Sandilands A, McLean WHI, Irvine AD (2009) Filaggrin in atopic dermatitis. J Allergy Clin Immunol 124(3):R2–R6. PubMedCrossRefGoogle Scholar
  188. 188.
    Politi E, Angelakopoulou A, Grapsa D, Zande M, Stefanaki K, Panagiotou I, Roma E, Syrigou E (2016) Filaggrin and periostin expression is altered in eosinophilic esophagitis and normalized with treatment. J Pediatr Gastroenterol Nutr 65(1):47–52. CrossRefGoogle Scholar
  189. 189.
    Abdulnour-Nakhoul SM, Al-Tawil Y, Gyftopoulos AA, Brown KL, Hansen M, Butcher KF, Eidelwein AP, Noel RA, Rabon E, Posta A, Nakhoul NL (2013) Alterations in junctional proteins, inflammatory mediators and extracellular matrix molecules in eosinophilic esophagitis. Clin Immunol 148(2):265–278. PubMedCrossRefGoogle Scholar
  190. 190.
    Kottke MD (2006) The desmosome: cell science lessons from human diseases. J Cell Sci 119(5):797–806. PubMedCrossRefGoogle Scholar
  191. 191.
    Kottyan LC, Davis BP, Sherrill JD, Liu K, Rochman M, Kaufman K, Weirauch MT, Vaughn S, Lazaro S, Rupert AM, Kohram M, Stucke EM, Kemme KA, Magnusen A, He H, Dexheimer P, Chehade M, Wood RA, Pesek RD, Vickery BP, Fleischer DM, Lindbad R, Sampson HA, Mukkada VA, Putnam PE, Abonia JP, Martin LJ, Harley JB, Rothenberg ME (2014) Genome-wide association analysis of eosinophilic esophagitis provides insight into the tissue specificity of this allergic disease. Nat Genet 46(8):895–900. PubMedPubMedCentralCrossRefGoogle Scholar
  192. 192.
    Davis BP, Kottyan LC, Stucke E, Sherrill JD, Rothenberg ME (2015) Functional analysis of calpain-14 in eosinophilic esophagitis. J Allergy Clin Immunol 135(2):AB77. CrossRefGoogle Scholar
  193. 193.
    D'Mello RJ, Caldwell JM, Azouz NP, Wen T, Sherrill JD, Hogan SP, Rothenberg ME (2016) LRRC31 is induced by IL-13 and regulates kallikrein expression and barrier function in the esophageal epithelium. Mucosal Immunol 9(3):744–756. PubMedCrossRefGoogle Scholar
  194. 194.
    Fillon S, Robinson ZD, Colgan SP, Furuta GT (2009) Epithelial function in eosinophilic gastrointestinal diseases. Immunol Allergy Clin N Am 29(1):171–178. CrossRefGoogle Scholar
  195. 195.
    Lim DM, Narasimhan S, Michaylira CZ, Wang ML (2009) TLR3-mediated NF- B signaling in human esophageal epithelial cells. AJP Gastrointestin Liver Physiol 297(6):G1172–G1180. CrossRefGoogle Scholar
  196. 196.
    Mulder DJ, Lobo D, Mak N, Justinich CJ (2011) Expression of toll-like receptors 2 and 3 on esophageal epithelial cell lines and on eosinophils during esophagitis. Dig Dis Sci 57(3):630–642. PubMedCrossRefGoogle Scholar
  197. 197.
    Zhang X, Cheng E, Huo X, Yu C, Zhang Q, Pham TH, Wang DH, Spechler SJ, Souza RF (2012) Omeprazole blocks STAT6 binding to the eotaxin-3 promoter in eosinophilic esophagitis cells. PLoS One 7(11):e50037. PubMedPubMedCentralCrossRefGoogle Scholar
  198. 198.
    Ziegler SF (2010) The role of thymic stromal lymphopoietin (TSLP) in allergic disorders. Curr Opin Immunol 22(6):795–799. PubMedPubMedCentralCrossRefGoogle Scholar
  199. 199.
    Ziegler SF, Artis D (2010) Sensing the outside world: TSLP regulates barrier immunity. Nat Immunol 11(4):289–293. PubMedPubMedCentralCrossRefGoogle Scholar
  200. 200.
    Wong CK, Hu S, Cheung PFY, Lam CWK (2010) Thymic stromal lymphopoietin induces chemotactic and prosurvival effects in eosinophils. Am J Respir Cell Mol Biol 43(3):305–315. PubMedCrossRefGoogle Scholar
  201. 201.
    Allakhverdi Z, Comeau MR, Jessup HK, Yoon B-RP, Brewer A, Chartier S, Paquette N, Ziegler SF, Sarfati M, Delespesse G (2007) Thymic stromal lymphopoietin is released by human epithelial cells in response to microbes, trauma, or inflammation and potently activates mast cells. J Exp Med 204(2):253–258. PubMedPubMedCentralCrossRefGoogle Scholar
  202. 202.
    Bogiatzi SI, Fernandez I, Bichet JC, Marloie-Provost MA, Volpe E, Sastre X, Soumelis V (2007) Cutting edge: proinflammatory and Th2 cytokines synergize to induce thymic stromal lymphopoietin production by human skin keratinocytes. J Immunol 178(6):3373–3377. PubMedCrossRefGoogle Scholar
  203. 203.
    Smelter DF, Sathish V, Thompson MA, Pabelick CM, Vassallo R, Prakash YS (2010) Thymic stromal lymphopoietin in cigarette smoke-exposed human airway smooth muscle. J Immunol 185(5):3035–3040. PubMedPubMedCentralCrossRefGoogle Scholar
  204. 204.
    Oyoshi MK, Larson RP, Ziegler SF, Geha RS (2010) Mechanical injury polarizes skin dendritic cells to elicit a TH2 response by inducing cutaneous thymic stromal lymphopoietin expression. J Allergy Clin Immunol 126(5):976–984.e975. PubMedPubMedCentralCrossRefGoogle Scholar
  205. 205.
    Sherrill JD, Gao PS, Stucke EM, Blanchard C, Collins MH, Putnam PE, Franciosi JP, Kushner JP, Abonia JP, Assa'ad AH, Kovacic MB, Biagini Myers JM, Bochner BS, He H, Hershey GK, Martin LJ, Rothenberg ME (2010) Variants of thymic stromal lymphopoietin and its receptor associate with eosinophilic esophagitis. J Allergy Clin Immunol 126(1):160–165.e163. PubMedPubMedCentralCrossRefGoogle Scholar
  206. 206.
    Judd LM, Heine RG, Menheniott TR, Buzzelli J, O'Brien-Simpson N, Pavlic D, O'Connor L, Al Gazali K, Hamilton O, Scurr M, Collison AM, Mattes J, Allen KJ, Giraud AS (2016) Elevated IL-33 expression is associated with pediatric eosinophilic esophagitis, and exogenous IL-33 promotes eosinophilic esophagitis development in mice. Am J Physiol Gastrointest Liver Physiol 310(1):G13–G25. PubMedCrossRefGoogle Scholar
  207. 207.
    Travers J, Rochman M, Wen T, Rothenberg ME IL-33 is selectively expressed by esophageal basal layer epithelial cells during allergic inflammation. J Allergy Clin Immunol 137(2):AB228.
  208. 208.
    Johnston LK, Hsu CL, Krier-Burris RA, Chhiba KD, Chien KB, McKenzie A, Berdnikovs S, Bryce PJ (2016) IL-33 precedes IL-5 in regulating eosinophil commitment and is required for eosinophil homeostasis. J Immunol (Baltimore, Md : 1950) 197(9):3445–3453. CrossRefGoogle Scholar
  209. 209.
    Venturelli N, Lexmond WS, Ohsaki A, Nurko S, Karasuyama H, Fiebiger E, Oyoshi MK (2016) Allergic skin sensitization promotes eosinophilic esophagitis through the IL-33-basophil axis in mice. J Allergy Clin Immunol 138(5):1367–1380.e1365. PubMedCrossRefGoogle Scholar
  210. 210.
    Dellon ES, Kim HP, Sperry SLW, Rybnicek DA, Woosley JT, Shaheen NJ (2014) A phenotypic analysis shows that eosinophilic esophagitis is a progressive fibrostenotic disease. Gastrointest Endosc 79(4):577–585.e574. PubMedCrossRefGoogle Scholar
  211. 211.
    Schoepfer AM, Safroneeva E, Bussmann C, Kuchen T, Portmann S, Simon HU, Straumann A (2013) Delay in diagnosis of eosinophilic esophagitis increases risk for stricture formation in a time-dependent manner. Gastroenterology 145(6):1230–1236.e1232. PubMedCrossRefGoogle Scholar
  212. 212.
    Desai TK, Stecevic V, Chang C-H, Goldstein NS, Badizadegan K, Furuta GT (2005) Association of eosinophilic inflammation with esophageal food impaction in adults. Gastrointest Endosc 61(7):795–801. PubMedCrossRefGoogle Scholar
  213. 213.
    Lucendo AJ, Arias Á, De Rezende LC, Yagüe-Compadre JL, Mota-Huertas T, González-Castillo S, Cuesta RA, Tenias JM, Bellón T (2011) Subepithelial collagen deposition, profibrogenic cytokine gene expression, and changes after prolonged fluticasone propionate treatment in adult eosinophilic esophagitis: a prospective study. J Allergy Clin Immunol 128(5):1037–1046. PubMedCrossRefGoogle Scholar
  214. 214.
    Tomasek JJ, Gabbiani G, Hinz B, Chaponnier C, Brown RA (2002) Myofibroblasts and mechano-regulation of connective tissue remodelling. Nat Rev Mol Cell Biol 3(5):349–363. PubMedCrossRefGoogle Scholar
  215. 215.
    Conway S, Molkentin J (2008) Periostin as a heterofunctional regulator of cardiac development and disease. Curr Genomics 9(8):548–555. PubMedPubMedCentralCrossRefGoogle Scholar
  216. 216.
    Snider P, Hinton RB, Moreno-Rodriguez RA, Wang J, Rogers R, Lindsley A, Li F, Ingram DA, Menick D, Field L, Firulli AB, Molkentin JD, Markwald R, Conway SJ (2008) Periostin is required for maturation and extracellular matrix stabilization of noncardiomyocyte lineages of the heart. Circ Res 102(7):752–760. PubMedPubMedCentralCrossRefGoogle Scholar
  217. 217.
    Beppu L, Yang T, Luk M, Newbury RO, Palmquist J, Dohil R, Kurten RC, Broide DH, Aceves SS (2015) MMPs-2 and -14 are elevated in eosinophilic esophagitis and reduced following topical corticosteroid therapy. J Pediatr Gastroenterol Nutr 61(2):194–199. PubMedPubMedCentralCrossRefGoogle Scholar
  218. 218.
    Aceves SS (2014) Remodeling and fibrosis in chronic eosinophil inflammation. Dig Dis (Basel, Switzerland) 32(1–2):15–21. CrossRefGoogle Scholar
  219. 219.
    Rieder F, Nonevski I, Ma J, Ouyang Z, West G, Protheroe C, DePetris G, Schirbel A, Lapinski J, Goldblum J, Bonfield T, Lopez R, Harnett K, Lee J, Hirano I, Falk G, Biancani P, Fiocchi C (2014) T-helper 2 cytokines, transforming growth factor β1, and eosinophil products induce fibrogenesis and alter muscle motility in patients with eosinophilic esophagitis. Gastroenterology 146(5):1266–1277.e1269. PubMedPubMedCentralCrossRefGoogle Scholar
  220. 220.
    Mulder DJ, Pacheco I, Hurlbut DJ, Mak N, Furuta GT, MacLeod RJ, Justinich CJ (2008) FGF9-induced proliferative response to eosinophilic inflammation in oesophagitis. Gut 58(2):166–173. PubMedPubMedCentralCrossRefGoogle Scholar
  221. 221.
    Muir AB, Lim DM, Benitez AJ, Modayur Chandramouleeswaran P, Lee AJ, Ruchelli ED, Spergel JM, Wang M-L (2013) Esophageal epithelial and mesenchymal cross-talk leads to features of epithelial to mesenchymal transition in vitro. Exp Cell Res 319(6):850–859. PubMedCrossRefGoogle Scholar
  222. 222.
    Kagalwalla AF, Akhtar N, Woodruff SA, Rea BA, Masterson JC, Mukkada V, Parashette KR, Du J, Fillon S, Protheroe CA, Lee JJ, Amsden K, Melin-Aldana H, Capocelli KE, Furuta GT, Ackerman SJ (2012) Eosinophilic esophagitis: epithelial mesenchymal transition contributes to esophageal remodeling and reverses with treatment. J Allergy Clin Immunol 129(5):1387–1396.e1387. PubMedPubMedCentralCrossRefGoogle Scholar
  223. 223.
    Roman S, Hirano I, Kwiatek MA, Gonsalves N, Chen J, Kahrilas PJ, Pandolfino JE (2010) Manometric features of eosinophilic esophagitis in esophageal pressure topography. Neurogastroenterol Motil 23(3):208–e111. PubMedPubMedCentralCrossRefGoogle Scholar
  224. 224.
    Zeisberg M (2008) Fibroblasts emerge via epithelial-mesenchymal transition in chronic kidney fibrosis. Front Biosci 13(13):6991. PubMedCrossRefGoogle Scholar
  225. 225.
    Jiang M, Ku W-Y, Zhou Z, Dellon ES, Falk GW, Nakagawa H, Wang M-L, Liu K, Wang J, Katzka DA, Peters JH, Lan X, Que J (2015) BMP-driven NRF2 activation in esophageal basal cell differentiation and eosinophilic esophagitis. J Clin Investig 125(4):1557–1568. PubMedCrossRefGoogle Scholar
  226. 226.
    Fujiwara Y (2006) Roles of epidermal growth factor and Na+/H+ exchanger-1 in esophageal epithelial defense against acid-induced injury. AJP: Gastrointestinal and Liver Physiology 290(4):G665–G673. CrossRefGoogle Scholar
  227. 227.
    Straumann A, Conus S, Degen L, Frei C, Bussmann C, Beglinger C, Schoepfer A, Simon HU (2011) Long-term budesonide maintenance treatment is partially effective for patients with eosinophilic esophagitis. Clin Gastroenterol Hepatol 9(5):400–409.e401. PubMedCrossRefGoogle Scholar
  228. 228.
    Lieberman JA, Morotti RA, Konstantinou GN, Yershov O, Chehade M (2012) Dietary therapy can reverse esophageal subepithelial fibrosis in patients with eosinophilic esophagitis: a historical cohort. Allergy 67(10):1299–1307. PubMedCrossRefGoogle Scholar
  229. 229.
    Lin F, Yang X (2010) TGF-β signaling in aortic aneurysm: another round of controversy. J Genet Genomics 37(9):583–591. PubMedCrossRefGoogle Scholar
  230. 230.
    Fox VL, Nurko S, Teitelbaum JE, Badizadegan K, Furuta GT (2003) High-resolution EUS in children with eosinophilic “allergic” esophagitis. Gastrointest Endosc 57(1):30–36. PubMedCrossRefGoogle Scholar
  231. 231.
    Fontillón M, Lucendo AJ (2012) Transmural eosinophilic infiltration and fibrosis in a patient with non-traumatic Boerhaave’s syndrome due to eosinophilic esophagitis. Am J Gastroenterol 107(11):1762–1762. PubMedCrossRefGoogle Scholar
  232. 232.
    Lucendo AJ (2006) Motor disturbances participate in the pathogenesis of eosinophilic oesophagitis, beyond the fibrous remodelling of the oesophagus. Aliment Pharmacol Ther 24(8):1264–1267. PubMedCrossRefGoogle Scholar
  233. 233.
    Hill DA, Artis D (2010) Intestinal bacteria and the regulation of immune cell homeostasis. Annu Rev Immunol 28(1):623–667. PubMedPubMedCentralCrossRefGoogle Scholar
  234. 234.
    Benitez AJ, Hoffmann C, Muir AB, Dods KK, Spergel JM, Bushman FD, Wang ML (2015) Inflammation-associated microbiota in pediatric eosinophilic esophagitis. Microbiome 3(1):23. PubMedPubMedCentralCrossRefGoogle Scholar
  235. 235.
    Harris JK, Fang R, Wagner BD, Choe HN, Kelly CJ, Schroeder S, Moore W, Stevens MJ, Yeckes A, Amsden K, Kagalwalla AF, Zalewski A, Hirano I, Gonsalves N, Henry LN, Masterson JC, Robertson CE, Leung DY, Pace NR, Ackerman SJ, Furuta GT, Fillon SA (2015) Esophageal microbiome in eosinophilic esophagitis. PLoS One 10(5):e0128346. PubMedPubMedCentralCrossRefGoogle Scholar
  236. 236.
    Schlag C, Miehlke S, Heiseke A, Brockow K, Krug A, von Arnim U, Straumann A, Vieth M, Bussmann C, Mueller R, Greinwald R, Bajbouj M (2015) Peripheral blood eosinophils and other non-invasive biomarkers can monitor treatment response in eosinophilic oesophagitis. Aliment Pharmacol Ther 42(9):1122–1130. PubMedCrossRefGoogle Scholar
  237. 237.
    Hui Y, Chen S, Lombardo KA, Resnick MB, Mangray S, Matoso A (2016) ALOX15 immunohistochemistry aids in the diagnosis of eosinophilic esophagitis on pauci-eosinophilic biopsies in children. Pediatr Dev Pathol.
  238. 238.
    Saffari H, Leiferman KM, Clayton F, Baer K, Pease LF, Gleich GJ, Peterson KA (2016) Measurement of inflammation in eosinophilic esophagitis using an eosinophil peroxidase assay. Am J Gastroenterol 111(7):933–939. PubMedCrossRefGoogle Scholar
  239. 239.
    Katzka DA, Geno DM, Ravi A, Smyrk TC, Lao-Sirieix P, Miremadi A, Debiram I, O'Donovan M, Kita H, Kephart GM, Kryzer LA, Camilleri M, Alexander JA, Fitzgerald RC (2015) Accuracy, safety, and tolerability of tissue collection by cytosponge vs endoscopy for evaluation of eosinophilic esophagitis. Clin Gastroenterol Hepatol 13(1):77–83.e72. PubMedCrossRefGoogle Scholar
  240. 240.
    Furuta GT, Kagalwalla AF, Lee JJ, Alumkal P, Maybruck BT, Fillon S, Masterson JC, Ochkur S, Protheroe C, Moore W, Pan Z, Amsden K, Robinson Z, Capocelli K, Mukkada V, Atkins D, Fleischer D, Hosford L, Kwatia MA, Schroeder S, Kelly C, Lovell M, Melin-Aldana H, Ackerman SJ (2013) The oesophageal string test: a novel, minimally invasive method measures mucosal inflammation in eosinophilic oesophagitis. Gut 62(10):1395–1405. PubMedCrossRefGoogle Scholar

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© Springer Science+Business Media, LLC, part of Springer Nature 2018

Authors and Affiliations

  1. 1.Department of Internal Medicine, Division of ImmunologyUniversity of Iowa Hospitals and ClinicsIowa CityUSA

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