Abstract
Background and aims
Epidermal differential complex (EDC) proteins, such as filaggrin, involucrin, and loricrin, play key roles to protect the mucosal surface against invading pathogens. Eosinophilic esophagitis (EoE) is an allergic gastrointestinal disease that features eosinophilic infiltration of esophageal mucosa, though the function of EDC proteins in its pathogenesis remains unknown. The aim of this study was to investigate possible differences of EDC protein expression in the epithelium of the esophagus, pharynx, and tongue. Furthermore, we examined that expression in esophageal specimens obtained from patients with EoE.
Methods
For evaluating EDC protein expression in epithelium from different locations, we enrolled 72 patients who underwent surgical resection for esophageal, pharyngeal, or tongue squamous cell carcinoma. Pathological samples were used for analysis of expression by immunohistochemistry. In addition, samples were obtained from 10 patients with EoE and 11 healthy subjects, and compared for esophageal epithelial expression of EDC proteins.
Results
In epithelium samples obtained from the esophagus, pharynx, and tongue, the presence of EDC proteins was confirmed by immunohistochemistry analysis findings, though the expression patterns were notably different in comparison to that in epidermis samples. In EoE patients, the expression of involucrin was dramatically down-regulated in esophageal mucosa, whereas down-regulation of filaggrin and loricrin did not reach a statistically significant level.
Conclusion
EDC protein expression was clearly detected in pharyngoesophageal epithelium samples, while that of involucrin alone was markedly reduced in patients with EoE.
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References
Asher MI, Montefort S, Björkstén B, et al. Worldwide time trends in the prevalence of symptoms of asthma, allergic rhinoconjunctivitis, and eczema in childhood: ISAAC Phases One and Three repeat multicountry cross-sectional surveys. Lancet. 2006;368(9537):733–43.
Wesemann DR, Nagler CR. The Microbiome, timing, and barrier function in the context of allergic disease. Immunity. 2016;44(4):728–38.
Candi E, Schmidt R, Melino G. The cornified envelope: a model of cell death in the skin. Nat Rev Mol Cell Biol. 2005;6(4):328–40.
Kypriotou M, Huber M, Hohl D. The human epidermal differentiation complex: cornified envelope precursors, S100 proteins and the ‘fused genes’ family. Exp Dermatol. 2012;21(9):643–9.
Listwan P, Rothnagel JA. Keratin bundling proteins. Methods Cell Biol. 2004;78:817–27.
Eckert RL, Crish JF, Efimova T, et al. Regulation of involucrin gene expression. J Invest Dermatol. 2004;123(1):13–22.
Iizuka H, Takahashi H, Honma M, Ishida-Yamamoto A. Unique keratinization process in psoriasis: late differentiation markers are abolished because of the premature cell death. J Dermatol. 2004;31(4):271–6.
Marenholz I, Volz A, Ziegler A, et al. Genetic analysis of the epidermal differentiation complex (EDC) on human chromosome 1q21: chromosomal orientation, new markers, and a 6-Mb YAC contig. Genomics. 1996;37(3):295–302.
Kinoshita Y, Furuta K, Ishimaura N, et al. Clinical characteristics of Japanese patients with eosinophilic esophagitis and eosinophilic gastroenteritis. J Gastroenterol. 2013;48(3):333–9.
Rothenberg ME. Molecular, genetic, and cellular bases for treating eosinophilic esophagitis. Gastroenterology. 2015;148(6):1143–57.
Kinoshita Y, Ishimura N, Oshima N, et al. Recent progress in the research of eosinophilic esophagitis and gastroenteritis. Digestion. 2016;93(1):7–12.
Kinoshita Y, Ishimura N, Mishiro T, et al. Diagnosis and treatment of eosiniophilic esophagitis in Japan. Esophagus. 2016;. doi:10.1007/s10388-016-0550-8.
Ishimura N, Furuta K, Sato S, Ishihara S, Kinoshita Y. Limited role of allergy testing in patients with eosinophilic gastrointestinal disorders. J Gastroenterol Hepatol. 2013;28(8):1306–13.
Ishimura N, Shimura S, Jiao D, et al. Clinical features of eosinophilic esophagitis: differences between Asian and Western populations. J Gastroenterol Hepatol. 2015;30(Suppl 1):71–7.
Simon D, Radonjic-Hosli S, Straumann A, Yousefi S, Simon HU. Active eosinophilic esophagitis is characterized by epithelial barrier defects and eosinophil extracellular trap formation. Allergy. 2015;70(4):443–52.
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(2):536–47.
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(7):4033–41.
Wawrzyniak P, Akdis CA, Finkelman FD, Rothenberg ME. Advances and highlights in mechanisms of allergic disease in 2015. J Allergy Clin Immunol. 2016;137(6):1681–96.
Weidinger S, Illig T, Baurecht H, et al. Loss-of-function variations within the filaggrin gene predispose for atopic dermatitis with allergic sensitizations. J Allergy Clin Immunol. 2006;118(1):214–9.
Palmer CN, Irvine AD, Terron-Kwiatkowski A, et al. Common loss-of-function variants of the epidermal barrier protein filaggrin are a major predisposing factor for atopic dermatitis. Nat Genet. 2006;38(4):441–6.
Irvine AD, McLean WH, Leung DY. Filaggrin mutations associated with skin and allergic diseases. N Engl J Med. 2011;365(14):1315–27.
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. 2016. doi:10.1007/s00535-016-1213-1.
Vighi G, Marcucci F, Sensi L, Di Cara G, Frati F. Allergy and the gastrointestinal system. Clin Exp Immunol. 2008;153(Suppl 1):3–6.
Kim BE, Howell MD, Guttman-Yassky E, et al. TNF-alpha downregulates filaggrin and loricrin through c-Jun N-terminal kinase: role for TNF-alpha antagonists to improve skin barrier. J Invest Dermatol. 2011;131(6):1272–9.
McAleer MA, Irvine AD. The multifunctional role of filaggrin in allergic skin disease. J Allergy Clin Immunol. 2013;131(2):280–91.
Jiang M, Ku WY, Zhou Z, et al. BMP-driven NRF2 activation in esophageal basal cell differentiation and eosinophilic esophagitis. J Clin Invest. 2015;125(4):1557–68.
Shoda T, Morita H, Nomura I, et al. Comparison of gene expression profiles in eosinophilic esophagitis (EoE) between Japan and Western countries. Allergol Int. 2015;64(3):260–5.
Acknowledgements
We thank Akira Yasuda (Department of Medical Informatics, Shimane University School of Medicine) for support regarding statistical analysis. This study was supported by the Health and Labour Sciences Research Grants for research on intractable diseases from the Ministry of Health, Labour and Welfare of Japan.
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Ethical Statement
The present study was performed at the Shimane University Hospital in accordance with the Declaration of Helsinki and the protocol was approved by the ethics committee of the Shimane University School of Medicine. Written informed consent was obtained from all subjects. This study was registered with the University Hospital Medical Information Network (UMIN) clinical trials registry (UMIN 000022242).
Conflicts of interest
Yoshikazu Kinoshita has received honoraria from AstraZeneca, Daiichi-Sankyo, EA Pharma, Otsuka, and Takeda Pharmaceutical.
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Oshima, N., Ishihara, S., Fukuba, N. et al. Epidermal differentiation complex protein involucrin is down-regulated in eosinophilic esophagitis. Esophagus 14, 171–177 (2017). https://doi.org/10.1007/s10388-016-0568-y
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DOI: https://doi.org/10.1007/s10388-016-0568-y