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Immunohistochemical expression of filaggrin is decreased in proton pump inhibitor non-responders compared with proton pump inhibitor responders of eosinophilic esophagitis

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Abstract

Background

Eosinophilic esophagitis (EoE) is an allergic gastrointestinal disease that features eosinophilic infiltration of esophageal mucosa, but the role of barrier dysfunction of the epithelium in its pathogenesis remains to be elucidated. Clinically, EoE is divided into proton pump inhibitor-non-responders (PPI-NR) and PPI-responders (PPI-R). Our main aims were to investigate the differences of expression of epidermal differential complex (EDC) proteins and desmoglein that are considered to play important roles in formation of the epidermal skin barrier between these two conditions and to seek the usefulness of the differences in pathological diagnosis. Conventional histopathological findings and allergic background were also compared.

Methods

Twenty-nine PPI-NR and 44 PPI-R were recruited, and 35 reflux esophagitis patients were also enrolled. After clinical information and histopathological findings were reviewed, immunohistochemical expression of EDC proteins (filaggrin, loricrin, and involucrin) and desmoglein in all three groups were examined and semi-quantitatively scored.

Results

Regarding allergic conditions, the prevalence of asthma was significantly higher in PPI-NR than in PPI-R. Other allergic conditions showed no differences. Histopathological findings did not exhibit the statistical difference between PPI-NR and PPI-R. However, immunostaining score of filaggrin in PPI-NR was significantly lower than in PPI-R, although the expressions of involucrin, loricrin and desmoglein demonstrated no differences.

Conclusions

The results suggest a role of reduced filaggrin expression in the difference of effectiveness of PPI treatment between PPI-NR and PPI-R. Moreover, immunohistochemical determination of filaggrin expression in EoE patients could be informative in the clinical decision of how to treat the patients.

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References

  1. Kinoshita Y, Ishimura N, Oshima N, et al. Recent progress in the research of eosinophilic esophagitis and gastroenteritis. Digestion. 2016;93:7–12.

    Article  Google Scholar 

  2. Kinoshita Y, Oouchi S, Fujisawa T. Eosinophilic gastrointestinal diseases—pathogenesis, diagnosis, and treatment. Allergol Int. 2019;68:420–9.

    Article  CAS  Google Scholar 

  3. Cabanillas B, Novak N. Atopic dermatitis and filaggrin. Curr Opin Immunol. 2016;42:1–8.

    Article  CAS  Google Scholar 

  4. Thyssen JP, Kezic S. Causes of epidermal filaggrin reduction and their role in the pathogenesis of atopic dermatitis. J Allergy Clin Immunol. 2014;134:792–9.

    Article  CAS  Google Scholar 

  5. Blanchard C, Stucke EM, Burwinkel K, et al. Coordinate interaction between IL-13 and epithelial differentiation cluster genes in eosinophilic esophagitis. J Immunol. 2010;184:4033–41.

    Article  CAS  Google Scholar 

  6. Sherrill JD, Kc K, Wu D, et al. Desmoglein-1 regulates esophageal epithelial barrier function and immune responses in eosinophilic esophagitis. Mucosal Immunol. 2014;7:718–29.

    Article  CAS  Google Scholar 

  7. Lucendo AJ, Arias Á, Molina-Infante J. Efficacy of proton pump inhibitor drugs for inducing clinical and histologic remission in patients with symptomatic esophageal eosinophilia: A systematic review and meta-analysis. Clin Gastroenterol Hepatol. 2016;14:13–22.

    Article  CAS  Google Scholar 

  8. Molina-Infante J, Katzka DA, Gisbert JP. Review article: Proton pump inhibitor therapy for suspected eosinophilic oesophagitis. Aliment Pharmacol Ther. 2013;37:1157–64.

    Article  CAS  Google Scholar 

  9. Liacouras CA, Furuta GT, Hirano I, et al. Eosinophilic esophagitis: Updated consensus recommendations for children and adults. J Allergy Clin Immunol. 2011;128:3–20.

    Article  Google Scholar 

  10. Molina-Infante J, Rivas MD, Hernandez-Alonso M, et al. Proton pump inhibitor-responsive oesophageal eosinophilia correlates with downregulation of eotaxin-3 and Th2 cytokines overexpression. Aliment Pharmacol Ther. 2014;40:955–65.

    Article  CAS  Google Scholar 

  11. van Rhijn BD, Weijenborg PW, Verheij J, et al. Proton pump inhibitors partially restore mucosal integrity in patients with proton pump inhibitor-responsive esophageal eosinophilia but not eosinophilic esophagitis. Clin Gastroenterol Hepatol. 2014;12:1815–23.

    Article  Google Scholar 

  12. Jiao D, Ishimura N, Maruyama R, et al. Similarities and differences among eosinophilic esophagitis, proton-pump inhibitor-responsive esophageal eosinophilia, and reflux esophagitis: comparisons of clinical, endoscopic, and histopathological findings in Japanese patients. J Gastroenterol. 2017;52:203–10.

    Article  CAS  Google Scholar 

  13. Lucendo AJ, Molina-Infante J, Arias Á, et al. Guidelines on eosinophilic esophagitis: evidence-based statements and recommendations for diagnosis and management in children and adults. United Eur Gastroenterol J. 2017;5:335–58.

    Article  Google Scholar 

  14. Oshima N, Ishihara S, Fukuba N, et al. Epidermal differentiation complex protein involucrin is down-regulated in eosinophilic esophagitis. Esophagus. 2017;14:171–7.

    Article  Google Scholar 

  15. Matoso A, Mukkada VA, Lu S, et al. Expression microarray analysis identifies novel epithelial-derived protein markers in eosinophilic esophagitis. Mod Pathol. 2013;26:665–76.

    Article  CAS  Google Scholar 

  16. Wu L, Oshima T, Li M, et al. Filaggrin and tight junction proteins are crucial for IL-13-mediated esophageal barrier dysfunction. Am J Physiol Gastrointest Liver Physiol. 2018;315:G341–50.

    Article  CAS  Google Scholar 

  17. Politi E, Angelakopoulou A, Grapsa D, et al. Filaggrin and periostin expression is altered in eosinophilic esophagitis and normalized with treatment. J Pediatr Gastroenterol Nutr. 2017;65:47–52.

    Article  CAS  Google Scholar 

  18. Marietta EV, Geno DM, Smyrk TC, et al. Presence of intraepithelial food antigen in patients with active eosinophilic oesophagitis. Aliment Pharmacol Ther. 2017;45:427–33.

    Article  CAS  Google Scholar 

  19. Davis BP. Pathophysiology of eosinophilic esophagitis. Clin Rev Allergy Immunol. 2018;55:19–42.

    Article  CAS  Google Scholar 

  20. Muir AB, Wang JX, Nakagawa H. Epithelial-stromal crosstalk and fibrosis in eosinophilic esophagitis. J Gastroenterol. 2019;54:10–8.

    Article  CAS  Google Scholar 

  21. Hill DA, Spergel JM. The immunologic mechanisms of eosinophilic esophagitis. Curr. Allergy Asthma Rep. 2016;16:9. https://doi.org/10.1007/s11882-015-0592-3.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. Cheng E, Zhang X, Huo X, et al. Omeprazole blocks eotaxin-3 expression by oesophageal squamous cells from patients with eosinophilic oesophagitis and GORD. Gut. 2013;62:824–32.

    Article  CAS  Google Scholar 

  23. Zhang X, Cheng E, Huo X, et al. Omeprazole blocks STAT6 binding to the eotaxin-3 promoter in eosinophilic esophagitis cells. PLoS One. 2012;7:e50037.

    Article  CAS  Google Scholar 

  24. Tanaka F, Fukumoto S, Morisaki T, et al. Obesity and hiatal hernia may be non-allergic risk factors for esophageal eosinophilia in Japanese adults. Esophagus. 2019;16:309–15.

    Article  Google Scholar 

  25. Durrani SR, Mukkada VA, Guilbert TW. Eosinophilic esophagitis: an important comorbid condition of asthma? Clin Rev Allergy Immunol. 2018;55:56–64.

    Article  CAS  Google Scholar 

  26. González-Cervera J, Arias Á, Redondo-González O, et al. Association between atopic manifestations and eosinophilic esophagitis: a systematic review and meta-analysis. Ann Allergy Asthma Immunol Am Coll Allergy Asthma Immunol. 2017;118:582–90 (e2).

    Article  Google Scholar 

  27. Doucet-Ladevèze R, Holvoet S, Raymond F, et al. Transcriptomic analysis links eosinophilic esophagitis and atopic dermatitis. Front Pediatr. 2019;7:467. https://doi.org/10.3389/fped.2019.00467.

    Article  PubMed  PubMed Central  Google Scholar 

  28. Padia R, Curtin K, Peterson K, et al. Eosinophilic esophagitis strongly linked to chronic rhinosinusitis. Laryngoscope. 2016;126:1279–83.

    Article  Google Scholar 

  29. Iwakura N, Fujiwara Y, Tanaka F, et al. Basophil infiltration in eosinophilic oesophagitis and proton pump inhibitor-responsive oesophageal eosinophilia. Aliment Pharmacol Ther. 2015;41:776–84.

    Article  CAS  Google Scholar 

  30. Ishimura N, Kinoshita Y. Eosinophilic esophagitis in Japan: Focus on response to acid suppressive therapy. J Gastroenterol Hepatol. 2018;33:1016–22.

    Article  CAS  Google Scholar 

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Acknowledgements

We thank Ms. Hiroko Wada (Department of Pathology, Shimane University School of Medicine) for support in immunohistochemistry and Dr. Akira Yasuda (Department of Medical Informatics, Shimane University School of Medicine) for support in statistical analysis.

Author information

Authors and Affiliations

  1. Pathology Unit, Shimane University Hospital, 89-1 Enya-cho, Izumo, Shimane, 693-8501, Japan

    Nahoko Nagano & Noriyoshi Ishikawa

  2. Organ Pathology Unit, Department of Pathology, Shimane University School of Medicine, 89-1 Enya-cho, Izumo, Shimane, 693-8501, Japan

    Asuka Araki, Mamiko Nagase & Riruke Maruyama

  3. Shimane Environmental and Health Public Corporation, 1-4-6 Koshibara, Matsue, Shimane, 690-0012, Japan

    Kyoichi Adachi

  4. Department of Gastroenterology and Hepatology, Shimane University School of Medicine, 89-1 Enya-cho, Izumo, Shimane, 693-8501, Japan

    Norihisa Ishimura & Shunji Ishihara

  5. Steel Memorial Hirohata Hospital, 3-1 Yumesaki-cho, Hirohata-ku, Himeji, Hyogo, 671-1122, Japan

    Yoshikazu Kinoshita

Authors
  1. Nahoko Nagano
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  2. Asuka Araki
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  9. Riruke Maruyama
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Contributions

Conceptualization: NN; AA; KA; NI; SI; YK; RM; Methodology: NN; AA; NI; MN; RM. Formal analysis and investigation: NN; AA, NI; KA; RM. Writing—original draft preparation: NN. Writing—review and editing: AA, KA; NI; RM. Supervision: SI; YK; RM.

Corresponding author

Correspondence to Asuka Araki.

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Ethical statement

The present study was performed at Shimane University Hospital in accordance with the Declaration of Helsinki, and the protocol was approved by the ethics committee of Shimane University School of Medicine. Written informed consent was obtained from all subjects.

Conflict of interest

Yoshikazu Kinoshita has received research funding from EA Pharma Co., Ltd., ZERIA Pharmaceutical Co., Ltd., and honorarium from EA Pharma Co., Ltd., Astellas Pharma Inc., AstraZeneca K.K., Mylan N.V., ZERIA Pharmaceutical Co., Ltd., Otsuka Pharmaceutical Co., Ltd., Takeda Pharmaceutical Co., Ltd., Daiichi-Sankyo Co., Ltd. Shunji Ishihara has received research funding from Takeda Pharmaceutical Co., Ltd., Astellas Pharma Inc., EA Pharma Co., Ltd., Janssen Pharmaceutical K.K., ZERIA Pharmaceutical Co., Ltd., and lecture fees from Takeda Pharmaceutical Co., Ltd. The other authors have no conflicts of interest and received no financial support for this study.

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Nagano, N., Araki, A., Ishikawa, N. et al. Immunohistochemical expression of filaggrin is decreased in proton pump inhibitor non-responders compared with proton pump inhibitor responders of eosinophilic esophagitis. Esophagus 18, 362–371 (2021). https://doi.org/10.1007/s10388-020-00781-2

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