Immune system and zinc are associated with recurrent aphthous stomatitis. An assessment using a network-based approach.

  • Cesar Rivera Department of Biomedical Sciences, Faculty of Health Sciences, University of Talca, Talca. Department of Oral Diagnosis, Piracicaba Dental School, University of Campinas, Piracicaba. Brazilian Biosciences National Laboratory (LNBio), National Center for Research in Energy and Materials (CNPEM), Campinas, São Paulo.


Objective: The aim of this research was to identify genes, proteins and processes from the biomedical information published on recurrent aphthous stomatitis (RAS) using network-based foci. Methods: The clinical context was defined using MeSH terms for RAS and biomarkers, combined with words associated with risk. A set of protein coding genes was prioritized using the Génie web server and classified with PANTHER. For defining biologically relevant proteins, protein-protein interaction networks were constructed using Reactome database and Cytoscape. Top 20 proteins were then subjected to functional enrichment using STRING. Results: From 1,075,576 gene-abstract links, 1,491 genes were prioritized. Proteins were related to signaling molecule proteins (n=221), receptor proteins (n=221) and nucleic acid binding proteins (n=169). The network constructed with these proteins included 3,963 nodes and functional analysis showed that main processes involved immune system and zinc ion binding function. Conclusions: For the first time, bioinformatics tools were used for integrating pathways and networks associated with RAS. Molecules and processes associated with immune system recur robustly in all analyzed information. The molecular zinc ion binding function could be an area for exploring more specific and effective therapeutic interventions.


1. Edgar NR, Saleh D, Miller RA. Recurrent Aphthous Stomatitis: A Review. J Clin Aesthet Dermatol. 2017;10(3):26–36.
2. Akintoye SO, Greenberg MS. Recurrent aphthous stomatitis. Dent Clin North Am. 2014;58(2):281–97.
3. Rivera C, Jones-Herrera C, Vargas P, Venegas B, Droguett D. Oral diseases: a 14-year experience of a Chilean institution with a systematic review from eight countries. Med Oral Patol Oral Cir Bucal. 2017;22(3):e297–e306.
4. Preeti L, Magesh K, Rajkumar K, Karthik R. Recurrent aphthous stomatitis. J Oral Maxillofac Pathol. 2011;15(3):252–6.
5. Jin LJ, Lamster IB, Greenspan JS, Pitts NB, Scully C, Warnakulasuriya S. Global burden of oral diseases: emerging concepts, management and interplay with systemic health. Oral Dis. 2016;22(7):609–19.
6. Riera Matute G, Riera Alonso E. [Recurrent aphthous stomatitis in Rheumatology] Reumatol Clin. 2011;7(5):323–8.
7. Dan S, Jinwei Z, Qiang Z, Jianwei S, Weijun Z. Exploring the Molecular Mechanism and Biomarker of Recurrent Aphthous Stomatitis Based on Gene Expression Microarray. Clin Lab. 2017;63(2):249–253.
8. Donnard E, Barbosa-Silva A, Guedes RL, Fernandes GR, Velloso H, Kohn MJ, Andrade-Navarro MA, Ortega JM. Preimplantation development regulatory pathway construction through a text-mining approach. BMC Genomics. 2011;12(Suppl 4):S3.
9. Barabási AL, Gulbahce N, Loscalzo J. Network medicine: a network-based approach to human disease. Nat Rev Genet. 2011;12(1):56–68.
10. Fontaine JF, Priller F, Barbosa-Silva A, Andrade-Navarro MA. Génie: literature-based gene prioritization at multi genomic scale. Nucleic Acids Res. 2011;39(suppl 2):W455–61.
11. Mi H, Huang X, Muruganujan A, Tang H, Mills C, Kang D, Thomas PD. PANTHER version 11: expanded annotation data from Gene Ontology and Reactome pathways, and data analysis tool enhancements. Nucleic Acids Res. 2017;45(D1):D183–9.
12. Mi H, Muruganujan A, Casagrande JT, Thomas PD. Large-scale gene function analysis with the PANTHER classification system. Nat Protoc. 2013;8(8):1551–66.
13. Muetze T, Goenawan IH, Wiencko HL, Bernal-Llinares M, Bryan K, Lynn DJ. Contextual Hub Analysis Tool (CHAT): A Cytoscape app for identifying contextually relevant hubs in biological networks. F1000Res. 2016;5
14. Fabregat A, Sidiropoulos K, Garapati P, Gillespie M, Hausmann K, Haw R, Jassal B, Jupe S, Korninger F, McKay S, Matthews L, May B, Milacic M, Rothfels K, Shamovsky V, Webber M, Weiser J, Williams M, Wu G, Stein L, Hermjakob H, D’Eustachio P. The Reactome pathway Knowledgebase. Nucleic Acids Res. 2016;44(D1):D481–7.
15. Szklarczyk D, Franceschini A, Wyder S, Forslund K, Heller D, Huerta-Cepas J, Simonovic M, Roth A, Santos A, Tsafou KP, Kuhn M, Bork P, Jensen LJ, von Mering C. STRING v10: protein–protein interaction networks, integrated over the tree of life. Nucleic Acids Res. 2015;43(D1):D447–52.
16. Pletscher-Frankild S, Pallejà A, Tsafou K, Binder JX, Jensen LJ. DISEASES: text mining and data integration of disease-gene associations. Methods. 2015;74(1):83–9.
17. Chattopadhyay A, Chatterjee S. Risk indicators for recurrent aphthous ulcers among adults in the US. Community Dent Oral Epidemiol. 2007;35(2):152–9.
18. Baccaglini L, Lalla RV, Bruce AJ, Sartori-Valinotti JC, Latortue MC, Carrozzo M, Rogers RS 3rd. Urban legends: recurrent aphthous stomatitis. Oral Dis. 2011;17(8):755–70.
19. Vidal M, Cusick ME, Barabási AL. Interactome networks and human disease. Cell. 2011;144(6):986–98.
20. Avci E, Akarslan ZZ, Erten H, Coskun-Cevher S. Oxidative stress and cellular immunity in patients with recurrent aphthous ulcers. Braz J Med Biol Res. 2014;47(5):355–60.
21. Brocklehurst P, Tickle M, Glenny AM, Lewis MA, Pemberton MN, Taylor J, Walsh T, Riley P, Yates JM. Systemic interventions for recurrent aphthous stomatitis (mouth ulcers) Cochrane Database Syst Rev. 2012;(9):CD005411.
22. Prasad AS. Zinc in human health: effect of zinc on immune cells. Mol Med. 2008;14(5-6):353–7.
23. Slebioda Z, Szponar E, Kowalska A. Etiopathogenesis of recurrent aphthous stomatitis and the role of immunologic aspects: literature review. Arch Immunol Ther Exp. 2014;62(3):205–15.
24. Ozler GS. Zinc deficiency in patients with recurrent aphthous stomatitis: a pilot study. J Laryngol Otol. 2014;128(6):531–3.
25. Orbak R, Cicek Y, Tezel A, Dogru Y. Effects of zinc treatment in patients with recurrent aphthous stomatitis. Dent Mater J. 2003;22(1):21–9.
26. Endre L. Recurrent aphthous ulceration with zinc deficiency and cellular immune deficiency. Oral Surg Oral Med Oral Pathol. 1991;72(5):559–61.
How to Cite
RIVERA, Cesar. Immune system and zinc are associated with recurrent aphthous stomatitis. An assessment using a network-based approach.. Journal of Oral Research, [S.l.], v. 6, n. 9, p. 245-251, sep. 2017. ISSN 0719-2479. Available at: <>. Date accessed: 24 feb. 2024. doi:


recurrent aphthous stomatitis; pathogenesis; protein interaction maps; immune system; zinc.