Eosinophilic esophagitis (EoE): Genetics and immunopathogenesis
- Marc E Rothenberg, MD, PhD
Marc E Rothenberg, MD, PhD
- Professor of Pediatrics
- Cincinnati Children's Hospital Medical Center
- University of Cincinnati College of Medicine
Eosinophilic esophagitis (EoE) is a chronic, immune/antigen-mediated esophageal disease characterized clinically by symptoms related to esophageal dysfunction and histologically by eosinophil-predominant inflammation . The pathogenesis of EoE is the result of an interplay between genetic, environmental, and host immune system factors.
This topic reviews the genetics and immunopathogenesis underlying EoE. The clinical features, diagnosis, and management of EoE are discussed in greater detail separately. (See "Clinical manifestations and diagnosis of eosinophilic esophagitis" and "Allergy testing in eosinophilic esophagitis" and "Treatment of eosinophilic esophagitis" and "Dietary management of eosinophilic esophagitis".)
The pathogenesis of EoE is incompletely understood but involves genetic, environmental, and host immune system factors. Differentiating gastroesophageal reflux disease (GERD), proton pump inhibitor-responsive esophageal eosinophilia (PPI-REE), and EoE is reviewed in greater detail separately. (See "Clinical manifestations and diagnosis of eosinophilic esophagitis", section on 'Distinction from GERD'.)
The esophagus is normally devoid of eosinophils, although they are permanent residents in the rest of the gastrointestinal tract beginning during early embryonic development. Thus, the finding of esophageal eosinophils denotes pathology, typically EoE or GERD [2,3]. The diagnosis of EoE requires the presence of esophageal eosinophilia that is resistant to PPI therapy, but it is now appreciated that a substantial number of patients with esophageal eosinophilia can respond to PPI therapy. This entity is now referred to as PPI-responsive esophageal eosinophilia (PPI-REE) .
Antigenic proteins, typically derived from food and less commonly from inhaled proteins, trigger an adaptive T helper type 2 (Th2) cell-mediated response that produces cytokines, such as interleukin (IL)-5 and IL-13 . IL-13 subsequently triggers resident cells, such as esophageal epithelial cells, to produce a large set of proteins. The most strongly induced gene in this process is eotaxin-3, which in turn recruits eosinophils from the peripheral blood into the tissue . Antigen-driven Th2 cells also produce IL-5, which is a chief eosinophil growth and activation factor that primes eosinophils to have enhanced responsiveness to eotaxin-3 and prolongs their cellular survival.
- Liacouras CA, Furuta GT, Hirano I, et al. Eosinophilic esophagitis: updated consensus recommendations for children and adults. J Allergy Clin Immunol 2011; 128:3.
- Fox VL, Nurko S, Furuta GT. Eosinophilic esophagitis: it's not just kid's stuff. Gastrointest Endosc 2002; 56:260.
- Rothenberg ME. Eosinophilic gastrointestinal disorders (EGID). J Allergy Clin Immunol 2004; 113:11.
- Molina-Infante J, Bredenoord AJ, Cheng E, et al. Proton pump inhibitor-responsive oesophageal eosinophilia: an entity challenging current diagnostic criteria for eosinophilic oesophagitis. Gut 2016; 65:524.
- Hogan SP, Mishra A, Brandt EB, et al. A critical role for eotaxin in experimental oral antigen-induced eosinophilic gastrointestinal allergy. Proc Natl Acad Sci U S A 2000; 97:6681.
- Mishra A, Hogan SP, Lee JJ, et al. Fundamental signals that regulate eosinophil homing to the gastrointestinal tract. J Clin Invest 1999; 103:1719.
- Sampson HA. Food allergy. Part 2: diagnosis and management. J Allergy Clin Immunol 1999; 103:981.
- Sampson HA. Food allergy. Part 1: immunopathogenesis and clinical disorders. J Allergy Clin Immunol 1999; 103:717.
- Bischoff S, Crowe SE. Gastrointestinal food allergy: new insights into pathophysiology and clinical perspectives. Gastroenterology 2005; 128:1089.
- Straumann A, Bauer M, Fischer B, et al. Idiopathic eosinophilic esophagitis is associated with a T(H)2-type allergic inflammatory response. J Allergy Clin Immunol 2001; 108:954.
- Oyaizu N, Uemura Y, Izumi H, et al. Eosinophilic gastroenteritis. Immunohistochemical evidence for IgE mast cell-mediated allergy. Acta Pathol Jpn 1985; 35:759.
- Saffari H, Hoffman LH, Peterson KA, et al. Electron microscopy elucidates eosinophil degranulation patterns in patients with eosinophilic esophagitis. J Allergy Clin Immunol 2014; 133:1728.
- Sherrill JD, Rothenberg ME. Genetic and epigenetic underpinnings of eosinophilic esophagitis. Gastroenterol Clin North Am 2014; 43:269.
- Wright BL, Kulis M, Guo R, et al. Food-specific IgG4 is associated with eosinophilic esophagitis. J Allergy Clin Immunol 2016; 138:1190.
- Clayton F, Fang JC, Gleich GJ, et al. Eosinophilic esophagitis in adults is associated with IgG4 and not mediated by IgE. Gastroenterology 2014; 147:602.
- Zukerberg L, Mahadevan K, Selig M, Deshpande V. Oesophageal intrasquamous IgG4 deposits: an adjunctive marker to distinguish eosinophilic oesophagitis from reflux oesophagitis. Histopathology 2016; 68:968.
- Spergel JM, Beausoleil JL, Mascarenhas M, Liacouras CA. The use of skin prick tests and patch tests to identify causative foods in eosinophilic esophagitis. J Allergy Clin Immunol 2002; 109:363.
- Walsh SV, Antonioli DA, Goldman H, et al. Allergic esophagitis in children: a clinicopathological entity. Am J Surg Pathol 1999; 23:390.
- Caldwell JH, Sharma HM, Hurtubise PE, Colwell DL. Eosinophilic gastroenteritis in extreme allergy. Immunopathological comparison with nonallergic gastrointestinal disease. Gastroenterology 1979; 77:560.
- Caldwell JH, Tennenbaum JI, Bronstein HA. Serum IgE in eosinophilic gastroenteritis. Response to intestinal challenge in two cases. N Engl J Med 1975; 292:1388.
- Cello JP. Eosinophilic gastroenteritis--a complex disease entity. Am J Med 1979; 67:1097.
- Scudamore HH, Phillips SF, Swedlund HA, Gleich GJ. Food allergy manifested by eosinophilia, elevated immunoglobulin E level, and protein-losing enteropathy: the syndrome of allergic gastroenteropathy. J Allergy Clin Immunol 1982; 70:129.
- Furuta GT, Ackerman SJ, Wershil BK. The role of the eosinophil in gastrointestinal diseases. Curr Opin Gastroenterol 1995; 11:541.
- Iacono G, Carroccio A, Cavataio F, et al. Gastroesophageal reflux and cow's milk allergy in infants: a prospective study. J Allergy Clin Immunol 1996; 97:822.
- Sampson HA. Food allergy. JAMA 1997; 278:1888.
- Woodruff SA, Masterson JC, Fillon S, et al. Role of eosinophils in inflammatory bowel and gastrointestinal diseases. J Pediatr Gastroenterol Nutr 2011; 52:650.
- Kelly KJ, Lazenby AJ, Rowe PC, et al. Eosinophilic esophagitis attributed to gastroesophageal reflux: improvement with an amino acid-based formula. Gastroenterology 1995; 109:1503.
- Henderson CJ, Abonia JP, King EC, et al. Comparative dietary therapy effectiveness in remission of pediatric eosinophilic esophagitis. J Allergy Clin Immunol 2012; 129:1570.
- Akei HS, Mishra A, Blanchard C, Rothenberg ME. Epicutaneous antigen exposure primes for experimental eosinophilic esophagitis in mice. Gastroenterology 2005; 129:985.
- Prasad GA, Alexander JA, Schleck CD, et al. Epidemiology of eosinophilic esophagitis over three decades in Olmsted County, Minnesota. Clin Gastroenterol Hepatol 2009; 7:1055.
- Wang FY, Gupta SK, Fitzgerald JF. Is there a seasonal variation in the incidence or intensity of allergic eosinophilic esophagitis in newly diagnosed children? J Clin Gastroenterol 2007; 41:451.
- Almansa C, Krishna M, Buchner AM, et al. Seasonal distribution in newly diagnosed cases of eosinophilic esophagitis in adults. Am J Gastroenterol 2009; 104:828.
- Onbasi K, Sin AZ, Doganavsargil B, et al. Eosinophil infiltration of the oesophageal mucosa in patients with pollen allergy during the season. Clin Exp Allergy 2005; 35:1423.
- Antico A, Fante R. Esophageal hypereosinophilia induced by grass sublingual immunotherapy. J Allergy Clin Immunol 2014; 133:1482.
- Miehlke S, Alpan O, Schröder S, Straumann A. Induction of eosinophilic esophagitis by sublingual pollen immunotherapy. Case Rep Gastroenterol 2013; 7:363.
- Lucendo AJ, Arias A, Tenias JM. Relation between eosinophilic esophagitis and oral immunotherapy for food allergy: a systematic review with meta-analysis. Ann Allergy Asthma Immunol 2014; 113:624.
- Garcia-Zepeda EA, Rothenberg ME, Ownbey RT, et al. Human eotaxin is a specific chemoattractant for eosinophil cells and provides a new mechanism to explain tissue eosinophilia. Nat Med 1996; 2:449.
- Furuta GT, Sherman P. Eotaxin and eosinophilic homing to the gut. J Pediatr Gastroenterol Nutr 2000; 30:229.
- Blanchard C, Wang N, Stringer KF, et al. Eotaxin-3 and a uniquely conserved gene-expression profile in eosinophilic esophagitis. J Clin Invest 2006; 116:536.
- Blanchard C, Stucke EM, Rodriguez-Jimenez B, et al. A striking local esophageal cytokine expression profile in eosinophilic esophagitis. J Allergy Clin Immunol 2011; 127:208.
- Mishra A, Hogan SP, Brandt EB, Rothenberg ME. An etiological role for aeroallergens and eosinophils in experimental esophagitis. J Clin Invest 2001; 107:83.
- Lucendo AJ, De Rezende L, Comas C, et al. Treatment with topical steroids downregulates IL-5, eotaxin-1/CCL11, and eotaxin-3/CCL26 gene expression in eosinophilic esophagitis. Am J Gastroenterol 2008; 103:2184.
- Mishra A, Wang M, Pemmaraju VR, et al. Esophageal remodeling develops as a consequence of tissue specific IL-5-induced eosinophilia. Gastroenterology 2008; 134:204.
- Rothenberg ME. Biology and treatment of eosinophilic esophagitis. Gastroenterology 2009; 137:1238.
- Blanchard C, Stucke EM, Burwinkel K, et al. Coordinate interaction between IL-13 and epithelial differentiation cluster genes in eosinophilic esophagitis. J Immunol 2010; 184:4033.
- Zuo L, Fulkerson PC, Finkelman FD, et al. IL-13 induces esophageal remodeling and gene expression by an eosinophil-independent, IL-13R alpha 2-inhibited pathway. J Immunol 2010; 185:660.
- Zhu X, Wang M, Mavi P, et al. Interleukin-15 expression is increased in human eosinophilic esophagitis and mediates pathogenesis in mice. Gastroenterology 2010; 139:182.
- Furuta GT, Straumann A. Review article: the pathogenesis and management of eosinophilic oesophagitis. Aliment Pharmacol Ther 2006; 24:173.
- Gupta SK, Fitzgerald JF, Kondratyuk T, HogenEsch H. Cytokine expression in normal and inflamed esophageal mucosa: a study into the pathogenesis of allergic eosinophilic esophagitis. J Pediatr Gastroenterol Nutr 2006; 42:22.
- Mishra A, Hogan SP, Brandt EB, Rothenberg ME. IL-5 promotes eosinophil trafficking to the esophagus. J Immunol 2002; 168:2464.
- Blanchard C, Mingler MK, Vicario M, et al. IL-13 involvement in eosinophilic esophagitis: transcriptome analysis and reversibility with glucocorticoids. J Allergy Clin Immunol 2007; 120:1292.
- Kottyan LC, Davis BP, Sherrill JD, et al. Genome-wide association analysis of eosinophilic esophagitis provides insight into the tissue specificity of this allergic disease. Nat Genet 2014; 46:895.
- Davis BP, Stucke EM, Khorki ME, et al. Eosinophilic esophagitis-linked calpain 14 is an IL-13-induced protease that mediates esophageal epithelial barrier impairment. JCI Insight 2016; 1:e86355.
- Mishra A, Weaver TE, Beck DC, Rothenberg ME. Interleukin-5-mediated allergic airway inflammation inhibits the human surfactant protein C promoter in transgenic mice. J Biol Chem 2001; 276:8453.
- Mishra A, Rothenberg ME. Intratracheal IL-13 induces eosinophilic esophagitis by an IL-5, eotaxin-1, and STAT6-dependent mechanism. Gastroenterology 2003; 125:1419.
- Rothenberg ME, Spergel JM, Sherrill JD, et al. Common variants at 5q22 associate with pediatric eosinophilic esophagitis. Nat Genet 2010; 42:289.
- Abonia JP, Wen T, Stucke EM, et al. High prevalence of eosinophilic esophagitis in patients with inherited connective tissue disorders. J Allergy Clin Immunol 2013; 132:378.
- Sherrill JD, Gao PS, Stucke EM, et al. Variants of thymic stromal lymphopoietin and its receptor associate with eosinophilic esophagitis. J Allergy Clin Immunol 2010; 126:160.
- Mulder DJ, Pacheco I, Hurlbut DJ, et al. FGF9-induced proliferative response to eosinophilic inflammation in oesophagitis. Gut 2009; 58:166.
- Lucendo AJ, Arias A, De Rezende LC, et al. 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 2011; 128:1037.
- Niranjan R, Mavi P, Rayapudi M, et al. Pathogenic role of mast cells in experimental eosinophilic esophagitis. Am J Physiol Gastrointest Liver Physiol 2013; 304:G1087.
- Aceves SS, Newbury RO, Dohil R, et al. Esophageal remodeling in pediatric eosinophilic esophagitis. J Allergy Clin Immunol 2007; 119:206.
- Lu TX, Sherrill JD, Wen T, et al. MicroRNA signature in patients with eosinophilic esophagitis, reversibility with glucocorticoids, and assessment as disease biomarkers. J Allergy Clin Immunol 2012; 129:1064.
- Noel RJ, Putnam PE, Rothenberg ME. Eosinophilic esophagitis. N Engl J Med 2004; 351:940.
- Alexander ES, Martin LJ, Collins MH, et al. Twin and family studies reveal strong environmental and weaker genetic cues explaining heritability of eosinophilic esophagitis. J Allergy Clin Immunol 2014; 134:1084.
- Collins MH, Blanchard C, Abonia JP, et al. Clinical, pathologic, and molecular characterization of familial eosinophilic esophagitis compared with sporadic cases. Clin Gastroenterol Hepatol 2008; 6:621.
- Guajardo JR, Plotnick LM, Fende JM, et al. Eosinophil-associated gastrointestinal disorders: a world-wide-web based registry. J Pediatr 2002; 141:576.
- Sherrill JD, Kiran KC, Blanchard C, et al. Analysis and expansion of the eosinophilic esophagitis transcriptome by RNA sequencing. Genes Immun 2014; 15:361.
- Wen T, Stucke EM, Grotjan TM, et al. Molecular diagnosis of eosinophilic esophagitis by gene expression profiling. Gastroenterology 2013; 145:1289.