Abstract

Eosinophilic esophagitis (EoE) is a food allergy–associated inflammatory disease characterized by esophageal eosinophilia. Current management strategies for EoE are nonspecific, and thus there is a need to identify specific immunological pathways that could be targeted to treat this disease. EoE is associated with polymorphisms in the gene that encodes thymic stromal lymphopoietin (TSLP), a cytokine that promotes allergic inflammation, but how TSLP might contribute to EoE disease pathogenesis has been unclear. Here, we describe a new mouse model of EoE-like disease that developed independently of IgE, but was dependent on TSLP and basophils, as targeting TSLP or basophils during the sensitization phase limited disease. Notably, therapeutic TSLP neutralization or basophil depletion also ameliorated established EoE-like disease. In human subjects with EoE, we observed elevated TSLP expression and exaggerated basophil responses in esophageal biopsies, and a gain-of-function TSLP polymorphism was associated with increased basophil responses in patients with EoE. Together, these data suggest that the TSLP-basophil axis contributes to the pathogenesis of EoE and could be therapeutically targeted to treat this disease.

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References

  1. 1.

    Eosinophilic esophagitis in adults and children: evidence for a food allergy component in many patients. Curr. Opin. Allergy Clin. Immunol. 7, 274–278 (2007).

  2. 2.

    et al. Eosinophilic esophagitis: updated consensus recommendations for children and adults. J. Allergy Clin. Immunol. 128, 3–20.e26 (2011).

  3. 3.

    & Eosinophilic esophagitis: rapidly advancing insights. Annu. Rev. Med. 63, 421–434 (2012).

  4. 4.

    & Eosinophilic esophagitis: escalating epidemiology? J. Allergy Clin. Immunol. 115, 418–419 (2005).

  5. 5.

    et al. Eosinophilic esophagitis: a prevalent disease in the United States that affects all age groups. Gastroenterology 134, 1316–1321 (2008).

  6. 6.

    & Therapeutic concepts in adult and paediatric eosinophilic oesophagitis. Nat. Rev. Gastroenterol. Hepatol. 9, 697–704 (2012).

  7. 7.

    , & Eosinophilic esophagitis: allergic contribution, testing, and management. Curr. Gastroenterol. Rep. 14, 206–215 (2012).

  8. 8.

    , , & Elemental diet is an effective treatment for eosinophilic esophagitis in children and adolescents. Am. J. Gastroenterol. 98, 777–782 (2003).

  9. 9.

    & B cells, IgE and mechanisms of type I hypersensitivity in eosinophilic oesophagitis. Gut 59, 6–7 (2010).

  10. 10.

    et al. Common variants at 5q22 associate with pediatric eosinophilic esophagitis. Nat. Genet. 42, 289–291 (2010).

  11. 11.

    et al. Variants of thymic stromal lymphopoietin and its receptor associate with eosinophilic esophagitis. J. Allergy Clin. Immunol. 126, 160–165.e163 (2010).

  12. 12.

    The role of thymic stromal lymphopoietin (TSLP) in allergic disorders. Curr. Opin. Immunol. 22, 795–799 (2010).

  13. 13.

    et al. A genome-wide meta-analysis of genetic variants associated with allergic rhinitis and grass sensitization and their interaction with birth order. J. Allergy Clin. Immunol. 128, 996–1005 (2011).

  14. 14.

    et al. Genetic variants of TSLP and asthma in an admixed urban population. PLoS ONE 6, e25099 (2011).

  15. 15.

    et al. Genome-wide association study identifies three new susceptibility loci for adult asthma in the Japanese population. Nat. Genet. 43, 893–896 (2011).

  16. 16.

    et al. TSLP polymorphisms are associated with asthma in a sex-specific fashion. Allergy 65, 1566–1575 (2010).

  17. 17.

    et al. TSLP promotes interleukin-3–independent basophil haematopoiesis and type 2 inflammation. Nature 477, 229–233 (2011).

  18. 18.

    , & Functional heterogeneity in the basophil cell lineage. Adv. Immunol. 115, 141–159 (2012).

  19. 19.

    et al. Thymic stromal lymphopoietin-dependent basophils promote TH2 cytokine responses following intestinal helminth infection. J. Immunol. 189, 4371–4378 (2012).

  20. 20.

    et al. TSLP: an epithelial cell cytokine that regulates T cell differentiation by conditioning dendritic cell maturation. Annu. Rev. Immunol. 25, 193–219 (2007).

  21. 21.

    et al. Human epithelial cells trigger dendritic cell mediated allergic inflammation by producing TSLP. Nat. Immunol. 3, 673–680 (2002).

  22. 22.

    , , & Epicutaneous exposure to protein antigen and food allergy. Clin. Exp. Allergy 33, 1067–1075 (2003).

  23. 23.

    Update on risk factors for food allergy. J. Allergy Clin. Immunol. 129, 1187–1197 (2012).

  24. 24.

    & Filaggrin gene defects and risk of developing allergic sensitisation and allergic disorders: systematic review and meta-analysis. Br. Med. J. 339, b2433 (2009).

  25. 25.

    et al. Topical vitamin D3 and low-calcemic analogs induce thymic stromal lymphopoietin in mouse keratinocytes and trigger an atopic dermatitis. Proc. Natl. Acad. Sci. USA 103, 11736–11741 (2006).

  26. 26.

    et al. Induction of thymic stromal lymphopoietin expression in keratinocytes is necessary for generating an atopic dermatitis upon application of the active vitamin D3 analogue MC903 on mouse skin. J. Invest. Dermatol. 129, 498–502 (2009).

  27. 27.

    , , & TSLP produced by keratinocytes promotes allergen sensitization through skin and thereby triggers atopic march in mice. J. Invest. Dermatol. 133, 154–163 (2013).

  28. 28.

    et al. Long-term outcomes in pediatric-onset esophageal eosinophilia. J. Allergy Clin. Immunol. 128, 132–138 (2011).

  29. 29.

    et al. Optical coherence tomography. Science 254, 1178–1181 (1991).

  30. 30.

    et al. Characterization of buried glands before and after radiofrequency ablation by using 3-dimensional optical coherence tomography (with videos). Gastrointest. Endosc. 76, 32–40 (2012).

  31. 31.

    et al. Increased expression of eotaxin-3 distinguishes between eosinophilic esophagitis and gastroesophageal reflux disease. Hum. Pathol. 38, 1744–1753 (2007).

  32. 32.

    et al. A striking local esophageal cytokine expression profile in eosinophilic esophagitis. J. Allergy Clin. Immunol. 127, 208–217, 217.e1–7 (2011).

  33. 33.

    , , & Expression of mast cell-associated genes is upregulated in adult eosinophilic esophagitis and responds to steroid or dietary therapy. J. Allergy Clin. Immunol. 127, 1307–1308.e3 (2011).

  34. 34.

    et al. Activated eosinophils in esophagitis in children: a transmission electron microscopic study. J. Pediatr. Gastroenterol. Nutr. 25, 194–198 (1997).

  35. 35.

    , , & Mechanical injury polarizes skin dendritic cells to elicit a TH2 response by inducing cutaneous thymic stromal lymphopoietin expression. J. Allergy Clin. Immunol. 126, 976–984, 984.e1–5 (2010).

  36. 36.

    et al. Spontaneous atopic dermatitis in mice expressing an inducible thymic stromal lymphopoietin transgene specifically in the skin. J. Exp. Med. 202, 541–549 (2005).

  37. 37.

    et al. Intradermal administration of thymic stromal lymphopoietin induces a T cell- and eosinophil-dependent systemic TH2 inflammatory response. J. Immunol. 181, 4311–4319 (2008).

  38. 38.

    Anaphylaxis: lessons from mouse models. J. Allergy Clin. Immunol. 120, 506–515 (2007).

  39. 39.

    et al. Immunophenotypic characterization and quantification of the epithelial inflammatory infiltrate in eosinophilic esophagitis through stereology: an analysis of the cellular mechanisms of the disease and the immunologic capacity of the esophagus. Am. J. Surg. Pathol. 31, 598–606 (2007).

  40. 40.

    et al. Local B cells and IgE production in the oesophageal mucosa in eosinophilic oesophagitis. Gut 59, 12–20 (2010).

  41. 41.

    et al. Omalizumab in the treatment of eosinophilic esophagitis and food allergy. Eur. J. Pediatr. 170, 1471–1474 (2011).

  42. 42.

    et al. Anti-IgE treatment of eosinophil-associated gastrointestinal disorders. J. Allergy Clin. Immunol. 120, 594–601 (2007).

  43. 43.

    & Immunomodulatory therapy of eosinophil-associated gastrointestinal diseases. Clin. Exp. Immunol. 38, 1858–1865 (2008).

  44. 44.

    et al. A phase II, randomized, double-blind, parallel-group, placebo-controlled oral food challenge trial of Xolair (omalizumab) in peanut allergy. J. Allergy Clin. Immunol. 127, 1309–1310.e1 (2011).

  45. 45.

    et al. Role of mast cells and basophils in IgE responses and in allergic airway hyperresponsiveness. J. Immunol. 188, 1809–1818 (2012).

  46. 46.

    et al. Basophils are essential initiators of a novel type of chronic allergic inflammation. Blood 110, 913–920 (2007).

  47. 47.

    & Allergic asthma: influence of genetic and environmental factors. J. Biol. Chem. 286, 32883–32889 (2011).

  48. 48.

    , & Host genetic susceptibility, dysbiosis, and viral triggers in inflammatory bowel disease. Curr. Opin. Gastroenterol. 27, 321–327 (2011).

  49. 49.

    et al. Gene-environment interactions in chronic inflammatory disease. Nat. Immunol. 12, 273–277 (2011).

  50. 50.

    , , & The genetics of multiple sclerosis: an up-to-date review. Immunol. Rev. 248, 87–103 (2012).

  51. 51.

    & The link between allergies and eosinophilic esophagitis: implications for management strategies. Expert Rev. Clin. Immunol. 6, 101–109 (2010).

  52. 52.

    et al. Cytokine expression in healthy and inflamed mucosa: probing the role of eosinophils in the digestive tract. Inflamm. Bowel Dis. 11, 720–726 (2005).

  53. 53.

    , , & Epicutaneous antigen exposure primes for experimental eosinophilic esophagitis in mice. Gastroenterology 129, 985–994 (2005).

  54. 54.

    , , , & Esophageal functional impairments in experimental eosinophilic esophagitis. Am. J. Physiol. Gastrointest. Liver Physiol. 302, G1347–G1355 (2012).

  55. 55.

    , , & Significance of para-esophageal lymph nodes in food or aeroallergen-induced iNKT cell-mediated experimental eosinophilic esophagitis. Am. J. Physiol. Gastrointest. Liver Physiol. 302, G645–G654 (2012).

  56. 56.

    , , & Critical role for adaptive T cell immunity in experimental eosinophilic esophagitis in mice. J. Leukoc. Biol. 81, 916–924 (2007).

  57. 57.

    & Intratracheal IL-13 induces eosinophilic esophagitis by an IL-5, eotaxin-1, and STAT6-dependent mechanism. Gastroenterology 125, 1419–1427 (2003).

  58. 58.

    , , & IL-5 promotes eosinophil trafficking to the esophagus. J. Immunol. 168, 2464–2469 (2002).

  59. 59.

    et al. Reslizumab in children and adolescents with eosinophilic esophagitis: results of a double-blind, randomized, placebo-controlled trial. J. Allergy Clin. Immunol. 129, 456–463, 463.e1–3 (2012).

  60. 60.

    et al. Reslizumab for poorly controlled, eosinophilic asthma: a randomized, placebo-controlled study. Am. J. Respir. Crit. Care Med. 184, 1125–1132 (2011).

  61. 61.

    et al. Thymic stromal lymphopoietin overproduced by keratinocytes in mouse skin aggravates experimental asthma. Proc. Natl. Acad. Sci. USA 106, 1536–1541 (2009).

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Acknowledgements

We thank members of the Artis laboratory for discussions and critical reading of the manuscript. Research in the Artis lab is supported by the US National Institutes of Health (AI061570, AI087990, AI074878, AI095776, AI102942, AI095466, AI09560 and AI097333 to D.A.), the Swiss National Science Foundation Prospective and Advanced Research Fellowships (PBBEP3_130438 and PA00P3_136468 to M.N.), the US National Institutes of Health (T32-AI060516 and F32-AI098365 to E.D.T.W., T32-AR007465 and KL2-RR024132 to B.S.K., F32-AI085828 to M.C.S., AI091759 to M.G.N. and K08-AI089982 to A.C.), the Australian National Health and Medical Research Council Overseas Biomedical Fellowship (613718 to P.R.G.), the State of Pennsylvania (SAP 4100042728 to P.M.S. and H.H.), the Burroughs Wellcome Fund Investigator in Pathogenesis of Infectious Disease Award (D.A.) and the Crohn's and Colitis Foundation of America (D.A.). This work was supported by the US National Institutes of Health/US National Institute of Diabetes and Digestive and Kidney Diseases P30 Center for Molecular Studies in Digestive and Liver Diseases (P30-DK050306), its pilot grant program and scientific core facilities (Molecular Pathology and Imaging, Molecular Biology, Cell Culture and Mouse) and the Joint Penn-Children's Hospital of Philadelphia Center in Digestive, Liver and Pancreatic Medicine and its pilot grant program. We also thank the Matthew J. Ryan Veterinary Hospital Pathology Lab and the Abramson Cancer Center Flow Cytometry and Cell Sorting Resource Laboratory (partially supported by US National Cancer Institute Comprehensive Cancer Center Support Grant (P30-CA016520)), the Skin Disease Research Center (supported by P30-AR057217) and the Electron Microscopy Resource Laboratory for technical advice and support. J.M.S. and K.R.R. acknowledge support from The Children's Hospital of Philadelphia Institutional Development Fund, and J.M.S. also acknowledges support from the US Department of Defense (A-16809.2). Human tissue samples were obtained by M.-L.W. and A.J.B., funded by Abbot Nutrition (ANUS1013). Research in the Zhou lab is supported by the US National Institutes of Health (R00EB010071) and the Lehigh University start-up fund. The studies described here were supported in part by the Institute for Translational Medicine and Therapeutics Transdisciplinary Program in Translational Medicine and Therapeutics (UL1-RR024134 from the US National Center for Research Resources). The authors also wish to thank P. Just and N. Ruiz at eBioscience for samples of flow cytometry reagents for human basophil panel development, support and invaluable technical advice. CD200R3-specific mAb (clone Ba103) was provided by H. Karasuyama (Tokyo Medical and Dental University Graduate School). The content is solely the responsibility of the authors and does not represent the official views of the US National Center for Research Resources or the US National Institutes of Health.

Author information

Author notes

    • Mario Noti
    •  & Elia D Tait Wojno

    These authors contributed equally to this work.

Affiliations

  1. Department of Microbiology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA.

    • Mario Noti
    • , Elia D Tait Wojno
    • , Brian S Kim
    • , Mark C Siracusa
    • , Paul R Giacomin
    • , Meera G Nair
    • , David A Hill
    •  & David Artis
  2. Institute for Immunology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA.

    • Mario Noti
    • , Elia D Tait Wojno
    • , Brian S Kim
    • , Mark C Siracusa
    • , Paul R Giacomin
    • , Meera G Nair
    • , David A Hill
    • , Jonathan M Spergel
    •  & David Artis
  3. Department of Dermatology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA.

    • Brian S Kim
  4. Centre for Biodiscovery and Molecular Development of Therapeutics, Queensland Tropical Health Alliance, James Cook University, Cairns, Queensland, Australia.

    • Paul R Giacomin
  5. Division of Biomedical Sciences, School of Medicine, University of California-Riverside, Riverside, California, USA.

    • Meera G Nair
  6. Division of Gastroenterology, Hepatology and Nutrition, Children′s Hospital of Philadelphia, Philadelphia, Pennsylvania, USA.

    • Alain J Benitez
    • , Amanda B Muir
    •  & Mei-Lun Wang
  7. Department of Pediatrics, Division of Allergy and Immunology, Children′s Hospital of Philadelphia, Philadelphia, Pennsylvania, USA.

    • Kathryn R Ruymann
    • , David A Hill
    • , Terri Brown-Whitehorn
    • , Antonella Cianferoni
    •  & Jonathan M Spergel
  8. Department of Pathology and Laboratory Medicine, Children′s Hospital of Philadelphia, Philadelphia, Pennsylvania, USA.

    • Kudakwashe R Chikwava
  9. The Sir William Dunn School of Pathology, The University of Oxford, Oxford, UK.

    • Amin E Moghaddam
    •  & Quentin J Sattentau
  10. Department of Electrical and Computer Engineering, Lehigh University, Bethlehem, Pennsylvania, USA.

    • Aneesh Alex
    •  & Chao Zhou
  11. Center for Photonics and Nanoelectronics, Lehigh University, Bethlehem, Pennsylvania, USA.

    • Aneesh Alex
    •  & Chao Zhou
  12. Bioengineering Program, Lehigh University, Bethlehem, Pennsylvania, USA.

    • Aneesh Alex
    •  & Chao Zhou
  13. Department of Pathology, Merck Research Laboratories, Palo Alto, California, USA.

    • Jennifer H Yearley
  14. Division of Gastroenterology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA.

    • Paul Menard-Katcher
    •  & Gary W Falk
  15. Laboratory for Cytokine Regulation, Research Center for Integrative Medical Science, RIKEN Yokohama Institute, Kanagawa, Japan.

    • Masato Kubo
  16. Division of Molecular Pathology, Research Institute for Biomedical Science, Tokyo University of Science, Chiba, Japan.

    • Masato Kubo
  17. Department of Immune Regulation, Tokyo Medical and Dental University Graduate School, Tokyo, Japan.

    • Kazushige Obata-Ninomiya
    •  & Hajime Karasuyama
  18. Japan Science and Technology Agency, Core Research for Evolutionary Science and Technology, Tokyo Medical and Dental University Graduate School, Tokyo, Japan.

    • Kazushige Obata-Ninomiya
    •  & Hajime Karasuyama
  19. Inflammation Research, Amgen, Seattle, Washington, USA.

    • Michael R Comeau
  20. Therapeutic Area Biology and Pharmacology, Merck Research Laboratories, Palo Alto, California, USA.

    • Rene de Waal Malefyt
  21. Center for Applied Genomics, Abramson Research Center, Children′s Hospital of Philadelphia, Philadelphia, Pennsylvania, USA.

    • Patrick M Sleiman
    •  & Hakon Hakonarson
  22. Division of Human Genetics, Abramson Research Center, Children′s Hospital of Philadelphia, Philadelphia, Pennsylvania, USA.

    • Patrick M Sleiman
    •  & Hakon Hakonarson
  23. Department of Pediatrics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA.

    • Patrick M Sleiman
    •  & Hakon Hakonarson
  24. Joint Penn-Children′s Hospital of Philadelphia Center for Digestive, Liver and Pancreatic Medicine, Perelman School of Medicine, University of Pennsylvania and Children′s Hospital of Philadelphia, Philadelphia, Pennsylvania, USA.

    • Gary W Falk
    • , Mei-Lun Wang
    • , Jonathan M Spergel
    •  & David Artis
  25. Center for Molecular Studies in Digestive and Liver Diseases, Department of Medicine, Division of Gastroenterology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA.

    • Gary W Falk
    • , Mei-Lun Wang
    • , Jonathan M Spergel
    •  & David Artis
  26. Department of Pathobiology, School of Veterinary Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA.

    • David Artis

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Contributions

M.N., E.D.T.W., B.S.K., M.C.S., P.R.G., M.G.N., A.B.M., A.A., C.Z. and D.A. designed and performed experiments. A.J.B., K.R.R., P.M.-K., A.C., G.W.F., M.-L.W. and J.M.S. obtained human pediatric and adult esophageal biopsies and peripheral blood samples, K.R.C. analyzed pediatric esophageal biopsy histology, and D.A.H. and T.B.-W. coordinated patient care and clinical studies. A.E.M. and Q.J.S. provided CPE, M.K. provided Baso-DTR mice, K.O.-N. and H.K. provided CD200R3-specific mAb, M.R.C. provided TSLPR-deficient mice and TSLP reagents, J.H.Y. and R.d.W.M. performed staining for human TSLP, and P.M.S. and H.H. provided genotype information on pediatric patients with EoE. M.N., E.D.T.W., B.S.K., M.C.S., P.R.G., A.A., C.Z., M.-L.W., J.M.S. and D.A. analyzed the data. M.N., E.D.T.W., M.C.S. and D.A. wrote the manuscript, and all authors critically reviewed the manuscript.

Competing interests

M.R.C. is an employee and shareholder of Amgen.

Corresponding author

Correspondence to David Artis.

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https://doi.org/10.1038/nm.3281

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