Pathophysiology of Eosinophilic Esophagitis

Abstract

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.

This is a preview of subscription content, access via your institution.

Fig. 1

Abbreviations

AD:

Atopic dermatitis

AEC:

Absolute eosinophil count

ALI:

Air-liquid interface

ALOX15:

Arachidonate-15 lipooxygenase

APCs:

Antigen-presenting cells

APT:

Atopy patch test

CAPN14:

Calpain 14

CDH26:

Cadherin-like 26

CPA3A:

Carboxypeptidase 3A

CRLF2 :

Cytokine receptor–like factor 2

CRS:

Chronic rhinosinusitis

CRTH2:

Chemoattractant receptor expressed on Th2 cells

CTDs:

Connective tissue disorders

DOCK8:

Dedicator Of cytokinesis 8

DSG1 :

Desmoglein 1

ECP:

Eosinophil cationic protein

EDC:

Epidermal differentiation complex

EDP:

EoE diagnostic panel

EMR,:

Electronic medical record

EMT:

Epithelial-to-mesenchymal transition

EoE:

Eosinophilic esophagitis

EPO:

Eosinophil peroxidase

EPX:

Eosinophil peroxidase

EST:

Esophageal string test

FCERI:

IgE Fragment crystallizable epsilon receptor 1

FLG:

Filaggrin

GERD:

Gastroesophageal reflux disease

GWAS:

Genome-wide association studies

HPF:

High-power field

IBD:

Inflammatory bowel disease

Ig:

Immunoglobulin

IL:

Interleukin

ILCs:

Innate lymphoid cells

iNKT:

Invariant natural killer T cells

IVL:

Involucrin

LDS:

Loetyz-Dietz syndrome

MBP:

Major basic protein

MIF:

Macrophage migration inhibitory factor

MIP-1:

Macrophage inflammatory protein 1

miRNAs:

MicroRNAs

OIT:

Oral immunotherapy

PAI-1:

Plasminogen activator inhibitor-1

PGD2:

Prostaglandin D2

PHTS:

PTEN hamartoma tumor syndrome

POSTN:

Periostin

PPI-REE:

PPI-responsive esophageal eosinophilia

PPI:

Proton pump inhibitor

PR:

Pathogenesis-related

RANTES:

Regulated on activation, normal T cells expressed and secreted

SAM:

Severe dermatitis, multiple allergies, and metabolic wasting

SERPINs:

Serine protease inhibitors

SPINKs:

Serine protease inhibitors, Kazal type

SPRR:

Small proline-rich repeat

SPT:

Skin prick test

STAT:

Signal transducer and activator of transcription

TGF-β:

Transforming growth factor beta

TH :

T helper type

TNF-α:

Tumor necrosis factor-α

TPSAB1:

Tryptase

TRAIL:

TNF-related apoptosis-inducing ligand

Tregs:

T regulatory cells

TSLP:

Thymic stromal lymphopoietin

TTG:

Tissue transglutaminase

TYK2:

Tyrosine-protein kinase-2

UC:

Ulcerative colitis

UPK1B:

Uroplakin 1B

References

  1. 1.

    Abonia JP, Rothenberg ME (2012) Eosinophilic esophagitis: rapidly advancing insights. Annu Rev Med 63(1):421–434. https://doi.org/10.1146/annurev-med-041610-134138

    PubMed  CAS  Article  Google 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. https://doi.org/10.1038/ajg.2014.316

    PubMed  Article  Google Scholar 

  3. 3.

    Eder W, Ege MJ, von Mutius E (2006) The asthma epidemic. N Engl J Med 355(21):2226–2235. https://doi.org/10.1056/NEJMra054308

    PubMed  CAS  Article  Google 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. https://doi.org/10.1016/j.jaci.2010.05.027

    PubMed  PubMed Central  Article  Google Scholar 

  5. 5.

    Noel RJ, Putnam PE, Rothenberg ME (2004) Eosinophilic esophagitis. N Engl J Med 351(9):940–941. https://doi.org/10.1056/NEJM200408263510924

    PubMed  CAS  Article  Google Scholar 

  6. 6.

    Sherrill JD, Rothenberg ME (2014) Genetic and epigenetic underpinnings of eosinophilic esophagitis. Gastroenterol Clin N Am 43(2):269–280. https://doi.org/10.1016/j.gtc.2014.02.003

    Article  Google 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. https://doi.org/10.1016/j.jaci.2011.02.040

    PubMed  Article  PubMed Central  Google 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. https://doi.org/10.1016/j.jaci.2014.08.043

    PubMed  CAS  Article  Google 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. https://doi.org/10.1586/eci.13.15

    PubMed  CAS  Article  Google 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. https://doi.org/10.11646/zootaxa.3887.1.4

    PubMed  Article  Google 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. https://doi.org/10.1111/j.1442-2050.2012.01363.x

    PubMed  CAS  Article  Google 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. https://doi.org/10.1097/MPG.0b013e3181788282

    PubMed  Article  Google 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. https://doi.org/10.1016/j.jaci.2011.05.006

    PubMed  PubMed Central  Article  Google 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. https://doi.org/10.1016/j.jaci.2013.02.030

    PubMed  Article  Google 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. https://doi.org/10.1016/j.jaci.2011.03.046

    PubMed  PubMed Central  CAS  Article  Google 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. https://doi.org/10.1172/jci26679

    PubMed  CAS  Article  Google 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. https://doi.org/10.4049/jimmunol.0903069

    PubMed  CAS  Article  Google 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. https://doi.org/10.1111/j.1398-9995.2009.02142.x

    PubMed  CAS  Article  Google 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. https://doi.org/10.1016/j.jaci.2010.04.037

    PubMed  PubMed Central  CAS  Article  Google 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. https://doi.org/10.1038/ncomms6593

    PubMed  PubMed Central  Article  Google 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. https://doi.org/10.1038/ng.547

    PubMed  PubMed Central  CAS  Article  Google 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. https://doi.org/10.3389/fgene.2014.00016

    PubMed  PubMed Central  CAS  Article  Google 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. https://doi.org/10.3389/fgene.2014.00401

    PubMed  PubMed Central  CAS  Article  Google 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. https://doi.org/10.1111/all.12879

    PubMed  CAS  Article  Google 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. https://doi.org/10.1016/j.jaci.2014.07.021

    PubMed  PubMed Central  Article  Google Scholar 

  26. 26.

    Rothenberg ME (2015) Molecular, genetic, and cellular bases for treating eosinophilic esophagitis. Gastroenterology 148(6):1143–1157. https://doi.org/10.1053/j.gastro.2015.02.002

    PubMed  PubMed Central  CAS  Article  Google 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. https://doi.org/10.1111/j.1747-0803.2006.00040.x

    PubMed  Article  Google 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. https://doi.org/10.1161/CIRCGENETICS.113.000280

    PubMed  CAS  Article  Google 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. https://doi.org/10.1038/ng.2739

    PubMed  PubMed Central  CAS  Article  Google 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. https://doi.org/10.1111/bjd.13247

    PubMed  CAS  Article  Google 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. https://doi.org/10.1038/mi.2013.90

    PubMed  PubMed Central  CAS  Article  Google 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. https://doi.org/10.1016/j.jaci.2013.11.039

    PubMed  PubMed Central  CAS  Article  Google 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. https://doi.org/10.1111/dote.12419

    PubMed  CAS  Article  Google Scholar 

  34. 34.

    Dharmaraj R, Hagglund K, Lyons H (2015) Eosinophilic esophagitis associated with celiac disease in children. BMC Res Notes 8(1):263. https://doi.org/10.1186/s13104-015-1256-z

    PubMed  PubMed Central  Article  Google 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. https://doi.org/10.1016/j.cgh.2015.02.018

    PubMed  PubMed Central  Article  Google 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. https://doi.org/10.3390/nu5093329

    PubMed  PubMed Central  CAS  Article  Google 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. https://doi.org/10.1186/1471-230X-13-96

    PubMed  PubMed Central  Article  Google 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. https://doi.org/10.1097/mpg.0000000000001437

    Article  Google Scholar 

  39. 39.

    Cianferoni A, Spergel J (2016) Eosinophilic esophagitis: a comprehensive review. Clin Rev Allergy Immunol 50(2):159–174. https://doi.org/10.1007/s12016-015-8501-z

    PubMed  CAS  Article  Google 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. https://doi.org/10.1038/ajg.2014.47

    PubMed  PubMed Central  Article  Google 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. https://doi.org/10.1097/MCG.0b013e31826df861

    PubMed  Article  Google 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. https://doi.org/10.1097/mpg.0b013e3181eb5a9f

    PubMed  PubMed Central  Article  Google 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. https://doi.org/10.1038/ajg.2012.6

    PubMed  PubMed Central  Article  Google 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. https://doi.org/10.1073/pnas.1412008111

    PubMed  PubMed Central  CAS  Article  Google 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. https://doi.org/10.1016/j.aller.2013.03.010

    CAS  Article  Google 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. https://doi.org/10.1097/mpg.0b013e318290d15a

    PubMed  Article  Google 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. https://doi.org/10.1038/ajg.2010.412

    PubMed  CAS  Article  Google 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. https://doi.org/10.1007/s00431-011-1540-4

    PubMed  CAS  Article  Google 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. https://doi.org/10.1189/jlb.1106653

    PubMed  CAS  Article  Google 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. https://doi.org/10.1053/j.gastro.2012.03.001

    PubMed  Article  Google Scholar 

  51. 51.

    Uzzaman A, Cho SH (2012) Chapter 28: classification of hypersensitivity reactions. Allergy Asthma Proc 33(3):96–99. https://doi.org/10.2500/aap.2012.33.3561

    PubMed  Article  Google 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. https://doi.org/10.1189/jlb.0110025

    PubMed  PubMed Central  CAS  Article  Google 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. https://doi.org/10.1074/jbc.m406037200

    PubMed  CAS  Article  Google 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. https://doi.org/10.1038/nm.3281

    PubMed  PubMed Central  CAS  Article  Google 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. https://doi.org/10.1016/j.jaci.2006.04.046

    PubMed  CAS  Article  Google 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. https://doi.org/10.1097/aci.0b013e32813aee4a

    PubMed  Article  Google 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. https://doi.org/10.1016/j.jaci.2006.10.044

    PubMed  Article  Google 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. https://doi.org/10.1016/s1081-1206(10)61151-9

    PubMed  Article  Google 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. https://doi.org/10.1016/S1542-3565(05)00885-2

    PubMed  Article  Google 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. https://doi.org/10.1067/mai.2002.121458

    PubMed  Article  Google 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. https://doi.org/10.1111/all.12157

    PubMed  CAS  Article  Google 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 https://doi.org/10.1016/j.jaci.2012.05.021

    PubMed  Article  Google 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. https://doi.org/10.1016/j.jaci.2012.03.023

    PubMed  PubMed Central  Article  Google 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. https://doi.org/10.1016/j.jaci.2015.02.038

    PubMed  Article  Google 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. https://doi.org/10.1016/j.jaci.2014.11.028

    PubMed  CAS  Article  Google 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. https://doi.org/10.1016/j.jaci.2016.12.110

  67. 67.

    Chehade M, Aceves SS (2010) Food allergy and eosinophilic esophagitis. Curr Opin Allergy Clin Immunol 10(3):231–237. https://doi.org/10.1097/aci.0b013e328338cbab

    PubMed  Article  Google 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. https://doi.org/10.1016/j.jaci.2014.02.004

    PubMed  CAS  Article  Google 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. https://doi.org/10.1016/j.jaci.2016.12.123

  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. https://doi.org/10.1016/j.anai.2014.08.004

    PubMed  Article  Google 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. https://doi.org/10.1016/j.anai.2010.10.010

    Article  Google 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. https://doi.org/10.1159/000355161

    PubMed  PubMed Central  Article  Google 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. https://doi.org/10.1159/000457796

    PubMed  Article  Google 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. https://doi.org/10.1053/j.gastro.2014.05.036

    PubMed  CAS  Article  Google 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. https://doi.org/10.1016/j.jaci.2016.02.024

    PubMed  PubMed Central  CAS  Article  Google Scholar 

  76. 76.

    Fogg MI, Ruchelli E, Spergel JM (2003) Pollen and eosinophilic esophagitis. J Allergy Clin Immunol 112(4):796–797. https://doi.org/10.1016/S0091-6749(03)01715-9

    PubMed  Article  Google 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. https://doi.org/10.1111/j.1365-2036.2009.04199.x

    PubMed  CAS  Article  Google 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):205–208

    PubMed  PubMed Central  Google Scholar 

  79. 79.

    Mishra A, Rothenberg ME (2003) Intratracheal interleukin-13 induces eosinophilic esophagitis (EE). J Allergy Clin Immunol 111(2):S278. https://doi.org/10.1016/s0091-6749(03)81000-x

    Article  Google 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. https://doi.org/10.1172/JCI10224

    PubMed  PubMed Central  CAS  Article  Google 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. https://doi.org/10.1016/j.cgh.2009.08.030

    PubMed  PubMed Central  Article  Google 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. https://doi.org/10.1016/j.cgh.2009.06.023

    PubMed  PubMed Central  Article  Google Scholar 

  83. 83.

    Dellon ES (2014) Epidemiology of eosinophilic esophagitis. Gastroenterol Clin N Am 43(2):201–218. https://doi.org/10.1016/j.gtc.2014.02.002

    Article  Google 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. https://doi.org/10.1038/ajg.2008.169

    PubMed  Article  Google 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. https://doi.org/10.1097/01.mcg.0000248019.16139.67

    PubMed  Article  Google 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. https://doi.org/10.1177/0194599810392655

    PubMed  Article  Google 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. https://doi.org/10.1016/j.anai.2016.03.017

    PubMed  Article  Google 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. https://doi.org/10.1016/j.jaci.2005.01.017

    PubMed  Article  Google 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. https://doi.org/10.1111/all.12257

    PubMed  CAS  Article  Google Scholar 

  90. 90.

    de Fraissinette A, Schmitt D, Thivolet J (1989) Langerhans cells of human mucosa. J Dermatol 16(4):255–262. https://doi.org/10.1111/j.1346-8138.1989.tb01261.x

    PubMed  Article  Google 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. https://doi.org/10.1111/j.1365-2222.2005.02303.x

    PubMed  CAS  Article  Google 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. https://doi.org/10.1002/lary.25798

    PubMed  Article  Google 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. https://doi.org/10.1046/j.1523-1747.1999.00720.x

    PubMed  CAS  Article  Google 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. https://doi.org/10.1111/j.1365-2222.2004.1953.x

    PubMed  CAS  Article  Google 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. https://doi.org/10.1046/j.1365-2133.1996.d01-1098.x

    PubMed  CAS  Article  Google 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. https://doi.org/10.1016/S0091-6749(99)70395-7

    PubMed  CAS  Article  Google 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. https://doi.org/10.1111/j.1398-9995.2004.00556.x

    PubMed  CAS  Article  Google 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. https://doi.org/10.1016/j.jaci.2014.07.049

    PubMed  CAS  Article  Google 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. https://doi.org/10.1053/j.gastro.2011.07.044

    PubMed  CAS  Article  Google Scholar 

  100. 100.

    Kottyan LC, Rothenberg ME (2017) Genetics of eosinophilic esophagitis. Mucosal Immunol 10(3):580–588. https://doi.org/10.1038/mi.2017.4

    PubMed  PubMed Central  CAS  Article  Google Scholar 

  101. 101.

    Corridoni D, Arseneau KO, Cominelli F (2014) Inflammatory bowel disease. Immunol Lett 161(2):231–235. https://doi.org/10.1016/j.imlet.2014.04.004

    PubMed  PubMed Central  CAS  Article  Google Scholar 

  102. 102.

    Xavier RJ, Podolsky DK (2007) Unravelling the pathogenesis of inflammatory bowel disease. Nature 448(7152):427–434. https://doi.org/10.1038/nature06005

    PubMed  CAS  Article  Google 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. https://doi.org/10.1152/ajpgi.00013.2012

    CAS  Article  Google 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. https://doi.org/10.1053/j.gastro.2007.10.002

    PubMed  Article  Google 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. https://doi.org/10.1097/mpg.0b013e3182182ff8

    PubMed  PubMed Central  Article  Google Scholar 

  106. 106.

    Davis BP, Rothenberg ME (2013) Antigen presentation by eosinophils in eosinophilic esophagitis? J Pediatr Gastroenterol Nutr 56(3):242. https://doi.org/10.1097/MPG.0b013e31827ab8d3

    PubMed  Article  Google 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. https://doi.org/10.1016/j.jaci.2010.04.009

    PubMed  PubMed Central  CAS  Article  Google 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. https://doi.org/10.1016/j.jaci.2010.08.050

    PubMed  CAS  Article  Google 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. https://doi.org/10.1053/j.gastro.2003.09.024

    PubMed  Article  Google 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. https://doi.org/10.1097/mpg.0b013e31806ab384

    PubMed  Article  Google 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. https://doi.org/10.1016/j.jaci.2006.10.016

    PubMed  CAS  Article  Google 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. https://doi.org/10.1183/09031936.00019810

    PubMed  CAS  Article  Google 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. https://doi.org/10.1016/j.autneu.2006.10.003

    PubMed  CAS  Article  Google 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. https://doi.org/10.1152/ajpgi.00070.2013

    CAS  Article  Google 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. https://doi.org/10.1016/j.jaci.2013.02.042

    PubMed  PubMed Central  CAS  Article  Google 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. https://doi.org/10.1016/j.jaci.2010.10.039

    PubMed  PubMed Central  CAS  Article  Google Scholar 

  117. 117.

    Goswami R, Kaplan MH (2011) A brief history of IL-9. J Immunol 186(6):3283–3288. https://doi.org/10.4049/jimmunol.1003049

    PubMed  PubMed Central  CAS  Article  Google 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. https://doi.org/10.1038/nature10329

    PubMed  PubMed Central  CAS  Article  Google 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. https://doi.org/10.1016/j.ajpath.2010.10.027

    PubMed  PubMed Central  CAS  Article  Google 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. https://doi.org/10.1067/mai.2001.119917

    PubMed  CAS  Article  Google 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):99–107

    PubMed  CAS  Google 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. https://doi.org/10.1016/j.immuni.2011.03.015

    PubMed  CAS  Article  Google 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. https://doi.org/10.1038/nm.1946

    PubMed  PubMed Central  CAS  Article  Google 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. https://doi.org/10.1002/eji.201141668

    PubMed  CAS  Article  Google 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. https://doi.org/10.1053/gast.2002.32998

    PubMed  CAS  Article  Google 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. https://doi.org/10.1097/01.pas.0000213392.49698.8c

    PubMed  Article  Google 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. https://doi.org/10.1016/j.jaci.2007.10.024

    PubMed  CAS  Article  Google 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. https://doi.org/10.1136/gut.2009.178020

    PubMed Central  CAS  Article  Google 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. https://doi.org/10.1111/j.1398-9995.2010.02525.x

    PubMed  Article  Google 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. https://doi.org/10.1111/cea.12201

    CAS  Article  Google 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. https://doi.org/10.1038/cti.2013.13

    CAS  Article  Google 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):334–345

    PubMed  CAS  Google Scholar 

  133. 133.

    Berin MC, Shreffler WG (2008) TH2 adjuvants: implications for food allergy. J Allergy Clin Immunol 121(6):1311–1320. https://doi.org/10.1016/j.jaci.2008.04.023

    PubMed  CAS  Article  Google 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. https://doi.org/10.1152/ajpgi.00223.2011

    CAS  Article  Google 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. https://doi.org/10.1126/science.1219328

    PubMed  PubMed Central  CAS  Article  Google Scholar 

  136. 136.

    Garn H, Renz H (2007) Epidemiological and immunological evidence for the hygiene hypothesis. Immunobiology 212(6):441–452. https://doi.org/10.1016/j.imbio.2007.03.006

    PubMed  CAS  Article  Google 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. https://doi.org/10.1038/ajg.2014.12

    PubMed  PubMed Central  CAS  Article  Google 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. https://doi.org/10.1016/j.jaci.2015.05.048

    PubMed  PubMed Central  CAS  Article  Google 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. https://doi.org/10.1038/ni.2104

    PubMed  CAS  Article  Google 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. https://doi.org/10.1016/j.jaci.2014.11.037

    PubMed  PubMed Central  CAS  Article  Google 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. https://doi.org/10.1053/j.gastro.2005.06.027

    PubMed  CAS  Article  Google Scholar 

  142. 142.

    Blanchard C, Rothenberg ME (2008) Basic pathogenesis of eosinophilic esophagitis. Gastrointest Endosc Clin N Am 18(1):133–143. https://doi.org/10.1016/j.giec.2007.09.016

    PubMed  PubMed Central  Article  Google 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. https://doi.org/10.1111/j.1572-0241.2008.01937.x

    PubMed  CAS  Article  Google 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. https://doi.org/10.1053/j.gastro.2010.03.057

    PubMed  PubMed Central  CAS  Article  Google 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. https://doi.org/10.1067/mai.2001.119149

    PubMed  CAS  Article  Google 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. https://doi.org/10.1136/gut.2009.178558

    CAS  Article  Google 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. https://doi.org/10.1007/s10620-005-9048-2

    PubMed  CAS  Article  Google 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. https://doi.org/10.1097/01.mib.0000172557.39767.53

    PubMed  Article  Google 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. https://doi.org/10.4049/jimmunol.1000471

    PubMed  PubMed Central  CAS  Article  Google 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. https://doi.org/10.1111/j.1365-2222.2005.02299.x

    PubMed  CAS  Article  Google 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. https://doi.org/10.1038/mi.2008.15

    PubMed  PubMed Central  CAS  Article  Google 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. https://doi.org/10.1038/mi.2013.90

    PubMed  CAS  Article  Google 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. https://doi.org/10.1371/journal.pone.0157376

    PubMed  PubMed Central  CAS  Article  Google 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. https://doi.org/10.1053/j.gastro.2010.07.048

    PubMed  CAS  Article  Google 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. https://doi.org/10.1126/scitranslmed.3006448

    CAS  Article  Google 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. https://doi.org/10.1016/j.jaci.2016.02.028

    PubMed  PubMed Central  CAS  Article  Google 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. https://doi.org/10.1371/journal.pone.0144651

    PubMed  PubMed Central  CAS  Article  Google 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. https://doi.org/10.1016/j.jaci.2015.03.031

    PubMed  PubMed Central  CAS  Article  Google 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. https://doi.org/10.1038/mi.2015.6

    PubMed  PubMed Central  CAS  Article  Google 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. https://doi.org/10.1038/icb.2015.30

    PubMed  PubMed Central  CAS  Article  Google 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. https://doi.org/10.1111/dote.12118

    PubMed  PubMed Central  Article  Google 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. https://doi.org/10.1038/nrd2266

    PubMed  CAS  Article  Google 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. https://doi.org/10.1111/all.12096

    PubMed  CAS  Article  Google 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. https://doi.org/10.1016/j.jaci.2006.09.045

    PubMed  CAS  Article  Google 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. https://doi.org/10.4049/jimmunol.174.8.5024

    PubMed  CAS  Article  Google 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. https://doi.org/10.1016/j.jaci.2016.01.048

    PubMed  PubMed Central  CAS  Article  Google 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. https://doi.org/10.1016/j.jaci.2016.12.108

  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. https://doi.org/10.1016/j.jaci.2016.12.114

  169. 169.

    Blanchard C (2015) Molecular pathogenesis of eosinophilic esophagitis. Curr Opin Gastroenterol 31(4):321–327. https://doi.org/10.1097/mog.0000000000000186

    PubMed  CAS  Article  Google 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. https://doi.org/10.1038/gene.2014.27

    PubMed  PubMed Central  CAS  Article  Google 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. https://doi.org/10.1371/journal.pone.0127755

    PubMed  PubMed Central  CAS  Article  Google 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. https://doi.org/10.1053/j.gastro.2013.08.046

    PubMed  PubMed Central  CAS  Article  Google 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. https://doi.org/10.1016/j.jaci.2014.08.043

    PubMed  CAS  Article  Google 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. https://doi.org/10.1016/j.jaci.2016.11.028

    PubMed  Article  Google 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. https://doi.org/10.1101/sqb.2006.71.013

    PubMed  CAS  Article  Google 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. https://doi.org/10.1016/j.jaci.2012.01.060

    PubMed  PubMed Central  CAS  Article  Google 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. https://doi.org/10.1371/journal.pone.0040676

    PubMed  PubMed Central  CAS  Article  Google 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. https://doi.org/10.1038/mi.2012.16

    PubMed  PubMed Central  CAS  Article  Google Scholar 

  179. 179.

    Odze RD (2009) Pathology of eosinophilic esophagitis: what the clinician needs to know. Am J Gastroenterol 104(2):485–490. https://doi.org/10.1038/ajg.2008.40

    PubMed  Article  Google 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. https://doi.org/10.1172/jci57416

    PubMed  CAS  Article  Google 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. https://doi.org/10.1136/jcp.2005.031922

    PubMed  PubMed Central  CAS  Article  Google 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. https://doi.org/10.1097/01.mpg.0000215312.78664.b9

    PubMed  Article  Google Scholar 

  183. 183.

    Lucendo AJ, Lucendo B (2010) An update on the immunopathogenesis of eosinophilic esophagitis. Expert Rev Gastroenterol Hepatol 4(2):141–148. https://doi.org/10.1586/egh.10.9

    PubMed  CAS  Article  Google 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. https://doi.org/10.1016/j.jaci.2016.11.042

    PubMed  Article  PubMed Central  Google 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. https://doi.org/10.1046/j.1523-1747.1999.00613.x

    PubMed  CAS  Article  Google 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. https://doi.org/10.1038/ng.358

    PubMed  PubMed Central  CAS  Article  Google 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. https://doi.org/10.1016/j.jaci.2009.07.013

    PubMed  CAS  Article  Google 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. https://doi.org/10.1097/mpg.0000000000001419

    Article  Google 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. https://doi.org/10.1016/j.clim.2013.05.004

    PubMed  CAS  Article  Google Scholar 

  190. 190.

    Kottke MD (2006) The desmosome: cell science lessons from human diseases. J Cell Sci 119(5):797–806. https://doi.org/10.1242/jcs.02888

    PubMed  CAS  Article  Google 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. https://doi.org/10.1038/ng.3033

    PubMed  PubMed Central  CAS  Article  Google 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. https://doi.org/10.1016/j.jaci.2014.12.1184

    Article  Google 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. https://doi.org/10.1038/mi.2015.98

    PubMed  CAS  Article  Google 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. https://doi.org/10.1016/j.iac.2008.09.003

    Article  Google 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. https://doi.org/10.1152/ajpgi.00065.2009

    CAS  Article  Google 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. https://doi.org/10.1007/s10620-011-1907-4

    PubMed  CAS  Article  Google 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. https://doi.org/10.1371/journal.pone.0050037

    PubMed  PubMed Central  CAS  Article  Google Scholar 

  198. 198.

    Ziegler SF (2010) The role of thymic stromal lymphopoietin (TSLP) in allergic disorders. Curr Opin Immunol 22(6):795–799. https://doi.org/10.1016/j.coi.2010.10.020

    PubMed  PubMed Central  CAS  Article  Google Scholar 

  199. 199.

    Ziegler SF, Artis D (2010) Sensing the outside world: TSLP regulates barrier immunity. Nat Immunol 11(4):289–293. https://doi.org/10.1038/ni.1852

    PubMed  PubMed Central  CAS  Article  Google 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. https://doi.org/10.1165/rcmb.2009-0168oc

    PubMed  CAS  Article  Google 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. https://doi.org/10.1084/jem.20062211

    PubMed  PubMed Central  CAS  Article  Google 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. https://doi.org/10.4049/jimmunol.178.6.3373

    PubMed  CAS  Article  Google 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. https://doi.org/10.4049/jimmunol.1000252

    PubMed  PubMed Central  CAS  Article  Google 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. https://doi.org/10.1016/j.jaci.2010.08.041

    PubMed  PubMed Central  CAS  Article  Google 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. https://doi.org/10.1016/j.jaci.2010.04.037

    PubMed  PubMed Central  CAS  Article  Google 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. https://doi.org/10.1152/ajpgi.00290.2015

    PubMed  CAS  Article  Google 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. https://doi.org/10.1016/j.jaci.2015.12.879

  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. https://doi.org/10.4049/jimmunol.1600611

    CAS  Article  Google 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. https://doi.org/10.1016/j.jaci.2016.02.034

    PubMed  CAS  Article  Google 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. https://doi.org/10.1016/j.gie.2013.10.027

    PubMed  Article  Google 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. https://doi.org/10.1053/j.gastro.2013.08.015

    PubMed  Article  Google 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. https://doi.org/10.1016/s0016-5107(05)00313-5

    PubMed  Article  Google 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. https://doi.org/10.1016/j.jaci.2011.08.007

    PubMed  CAS  Article  Google 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. https://doi.org/10.1038/nrm809

    PubMed  CAS  Article  Google Scholar 

  215. 215.

    Conway S, Molkentin J (2008) Periostin as a heterofunctional regulator of cardiac development and disease. Curr Genomics 9(8):548–555. https://doi.org/10.2174/138920208786847917

    PubMed  PubMed Central  CAS  Article  Google 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. https://doi.org/10.1161/circresaha.107.159517

    PubMed  PubMed Central  CAS  Article  Google 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. https://doi.org/10.1097/mpg.0000000000000668

    PubMed  PubMed Central  CAS  Article  Google Scholar 

  218. 218.

    Aceves SS (2014) Remodeling and fibrosis in chronic eosinophil inflammation. Dig Dis (Basel, Switzerland) 32(1–2):15–21. https://doi.org/10.1159/000357004

    Article  Google 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. https://doi.org/10.1053/j.gastro.2014.01.051

    PubMed  PubMed Central  CAS  Article  Google 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. https://doi.org/10.1136/gut.2008.157628

    PubMed  PubMed Central  CAS  Article  Google 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. https://doi.org/10.1016/j.yexcr.2012.12.002

    PubMed  CAS  Article  Google 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. https://doi.org/10.1016/j.jaci.2012.03.005

    PubMed  PubMed Central  CAS  Article  Google 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. https://doi.org/10.1111/j.1365-2982.2010.01633.x

    PubMed  PubMed Central  Article  Google Scholar 

  224. 224.

    Zeisberg M (2008) Fibroblasts emerge via epithelial-mesenchymal transition in chronic kidney fibrosis. Front Biosci 13(13):6991. https://doi.org/10.2741/3204

    PubMed  CAS  Article  Google 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. https://doi.org/10.1172/jci78850

    PubMed  Article  Google 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. https://doi.org/10.1152/ajpgi.00238.2005

    CAS  Article  Google 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. https://doi.org/10.1016/j.cgh.2011.01.017

    PubMed  CAS  Article  Google 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. https://doi.org/10.1111/j.1398-9995.2012.02881.x

    PubMed  CAS  Article  Google 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. https://doi.org/10.1016/s1673-8527(09)60078-3

    PubMed  CAS  Article  Google 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. https://doi.org/10.1067/mge.2003.33

    PubMed  Article  Google 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. https://doi.org/10.1038/ajg.2012.226

    PubMed  Article  Google 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. https://doi.org/10.1111/j.1365-2036.2006.03109.x

    PubMed  CAS  Article  Google Scholar 

  233. 233.

    Hill DA, Artis D (2010) Intestinal bacteria and the regulation of immune cell homeostasis. Annu Rev Immunol 28(1):623–667. https://doi.org/10.1146/annurev-immunol-030409-101330

    PubMed  PubMed Central  CAS  Article  Google 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. https://doi.org/10.1186/s40168-015-0085-6

    PubMed  PubMed Central  Article  Google 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. https://doi.org/10.1371/journal.pone.0128346

    PubMed  PubMed Central  CAS  Article  Google 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. https://doi.org/10.1111/apt.13386

    PubMed  CAS  Article  Google 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. https://doi.org/10.2350/16-05-1818-oa.1

  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. https://doi.org/10.1038/ajg.2016.184

    PubMed  CAS  Article  Google 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. https://doi.org/10.1016/j.cgh.2014.06.026

    PubMed  Article  Google 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. https://doi.org/10.1136/gutjnl-2012-303171

    PubMed  CAS  Article  Google Scholar 

Download references

Funding

No funding was used in the creation of this manuscript.

Author information

Affiliations

Authors

Corresponding author

Correspondence to Benjamin P. Davis.

Ethics declarations

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.

Rights and permissions

Reprints and Permissions

About this article

Verify currency and authenticity via CrossMark

Cite this article

Davis, B.P. Pathophysiology of Eosinophilic Esophagitis. Clinic Rev Allerg Immunol 55, 19–42 (2018). https://doi.org/10.1007/s12016-017-8665-9

Download citation

Keywords

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