Foxp3 gene expression in oral lichen planus: A clinicopathological study

Lei,Lei; Zhan,Lihua; Tan,Weixia; Chen,Shaohua; Li,Yangqiu; Reynolds,Mark

doi:10.3892/mmr.2014.1919

Foxp3 gene expression in oral lichen planus: A clinicopathological study

Authors:
- Lei Lei
- Lihua Zhan
- Weixia Tan
- Shaohua Chen
- Yangqiu Li
- Mark Reynolds
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Affiliations: Department of Stomatology, Medical College of Jinan University, Guangzhou, Guangdong 510632, P.R. China, Department of Stomatology, First Affiliated Hospital, Shenzhen, Guangdong 518008, P.R. China, DiWang Clinic of Shenzhen Arrail Dental, Shenzhen, Guangdong 518008, P.R. China, Institute of Hematology, Medical College, Jinan University, Guangzhou, Guangdong 510632, P.R. China, Department of Periodontics, University of Maryland, School of Dentistry, Baltimore, MA 21201, USA
Published online on: January 24, 2014 https://doi.org/10.3892/mmr.2014.1919
Pages: 928-934

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Abstract

CD4+CD25+ Forkhead‑box protein 3 (Foxp3+) regulatory T cells are important in oral lichen planus (OLP). The present study aimed to investigate Foxp3 expression in CD4+CD25+ T cells of peripheral blood mononuclear cells and oral lesions in patients diagnosed with OLP, who were grouped as OLP subtype, duration and relapse. Using quantitative polymerase chain reaction (qPCR), western blotting and immunohistochemistry, Foxp3 expression levels in explants of oral lesions and CD4+CD25+ T cells from 32 patients with OLP were measured and compared, with 10 healthy subjects as the control group. Foxp3 mRNA expression levels in the explants of oral lesions and circulating CD4+CD25+ T cells in patients with OLP were significantly higher than those in the control group (P<0.05). In patients with clinically erosive lesions, Foxp3 mRNA expression was significantly lower in circulating CD4+CD25+ T cells and tissue explants compared to patients with reticular lesions (P<0.01 and P<0.05, respectively), and lowest in patients with a history of OLP of >1 year or with a history of relapse (P<0.05 and P<0.01, respectively). Foxp3 protein levels in reticular OLP were significantly higher than those in erosive OLP and the control group. The incidence of Foxp3 protein expression in OLP tissues was 36.24±18.92 and 10.44±6.51% in normal oral mucosa (P=0.019). Atrophic/erosive OLP lesions showed a higher proportion of Foxp3‑expressing cells than that of reticular OLP lesions (P<0.05). This study indicated that Foxp3 expression in patients with OLP is associated with the severity and duration of the disorder, suggesting altered immune suppression in the development, clinical course and responsiveness to treatment.

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1	de Moura Castro Jacques C, Cardozo Pereira AL, Cabral MG, Cardoso AS and Ramos-e-Silva M: Oral lichen planus part I: epidemiology, clinics, etiology, immunopathogeny, and diagnosis. Skinmed. 2:342–347. 2003.PubMed/NCBI
2	Sugerman PB, Savage NW, Walsh LJ, et al: The pathogenesis of oral lichen planus. Crit Rev Oral Biol Med. 13:350–365. 2002. View Article : Google Scholar : PubMed/NCBI
3	Sugerman PB and Savage NW: Oral lichen planus: causes, diagnosis and management. Aust Dent J. 47:290–297. 2002. View Article : Google Scholar : PubMed/NCBI
4	Gadenne AS, Strucke R, Dunn D, Wagner M, Bleichner P and Bigby M: T-cell lines derived from lesional skin of lichen planus patients contain a distinctive population of T-cell receptor gamma delta-bearing cells. J Invest Dermatol. 103:347–351. 1994. View Article : Google Scholar
5	Sugerman PB, Savage NW and Seymour GJ: Phenotype and suppressor activity of T-lymphocyte clones extracted from lesions of oral lichen planus. Br J Dermatol. 131:319–324. 1994. View Article : Google Scholar : PubMed/NCBI
6	Roopashree MR, Gondhalekar RV, Shashikanth MC, et al: Pathogenesis of oral lichen planus - a review. J Oral Pathol Med. 39:729–734. 2010. View Article : Google Scholar : PubMed/NCBI
7	Khan A, Farah CS, Savage NW, et al: Th1 cytokines in oral lichen planus. J Oral Pathol Med. 32:77–83. 2003. View Article : Google Scholar : PubMed/NCBI
8	Lu R, Zhou G, Du G, Xu X, Yang J and Hu J: Expression of T-bet and GATA-3 in peripheral blood mononuclear cells of patients with oral lichen planus. Arch Oral Biol. 56:499–505. 2011. View Article : Google Scholar : PubMed/NCBI
9	Pindborg JJ, Reichart PA, Smith CJ, et al: Histological typing of cancer and precancer of the oral mucosa. World Health Organization International histological classification of tumours. 2nd edition. Springer; 25. Berlin, Germany: pp. 29–30. 1997
10	Sakaguchi S, Sakaguchi N, Asano M, Itoh M and Toda M: Immunologic self-tolerance maintained by activated T cells expressing IL-2 receptor alpha-chains (CD25). Breakdown of a single mechanism of self-tolerance causes various autoimmune diseases. J Immunol. 155:1151–1164. 1995.
11	Josefowicz SZ, Lu LF and Rudensky AY: Regulatory T cells: mechanisms of differentiation and function. Annu Rev Immunol. 30:531–564. 2012. View Article : Google Scholar : PubMed/NCBI
12	Wing K and Sakaguchi S: Regulatory T cells exert checks and balances on self-tolerance and autoimmunity. Nat Immunol. 11:7–13. 2010. View Article : Google Scholar : PubMed/NCBI
13	Taams LS, Palmer DB, Akbar AN, Robinson DS, Brown Z and Hawrylowicz CM: Regulatory T cells in human disease and their potential for therapeutic manipulation. Immunology. 118:1–9. 2006. View Article : Google Scholar : PubMed/NCBI
14	Hori S, Nomura T and Sakaguchi S: Control of regulatory T cell development by the transcription factor Foxp3. Science. 299:1057–1061. 2003. View Article : Google Scholar : PubMed/NCBI
15	Gavin MA, Rasmussen JP, Fontenot JD, et al: Foxp3-dependent programme of regulatory T-cell differentiation. Nature. 445:771–775. 2007. View Article : Google Scholar : PubMed/NCBI
16	Yagi H, Takashi Nomura T, Nakamura K, et al: Crucial role of Foxp3 in the development and function of human CD25⁺CD4⁺ regulatory T cells. Int Immunol. 16:1643–1656. 2004. View Article : Google Scholar : PubMed/NCBI
17	Bignone PA and Banham AH: Foxp3+ regulatory T cells as biomarkers in human malignancies. Expert Opin Biol Ther. 8:1897–1920. 2008.
18	Chen S, Yang L, Lu X, et al: Gene expression profiling of CD3gamma, delta, epsilon, and zeta chains in CD4(+) and CD8(+) T cells from human umbilical cord blood. Hematology. 15:230–235. 2010.PubMed/NCBI
19	Livak KJ and Schmittgen TD: Analysis of relative gene expression data using real-time quantitative PCR and the 2(−Delta Delta C(T)) Method. Methods. 25:402–408. 2001.
20	Livak KJ and Schmittgen TD: Analysis of relative gene expression data using real-time quantitative PCR and the 2(−Delta Delta C(T)) Method. Methods. 25:402–408. 2001.
21	Zhou XJ, Sugerman PB, Savage NW, Walsh LJ and Seymour GJ: Intra-epithelial CD8⁺ T cells and basement membrane disruption in oral lichen planus. J Oral Pathol Med. 31:23–27. 2002.PubMed/NCBI
22	Sugerman PB, Satterwhite K and Bigby M: Autocytotoxic T-cell clones in lichen planus. Br J Dermatol. 142:449–456. 2000. View Article : Google Scholar : PubMed/NCBI
23	Bascones-Ilundain C, Gonzalez-Moles MA, Esparza-Gómez G, Gil-Montoya JA and Bascones-Martínez A: Importance of apoptotic mechanisms in inflammatory infiltrate of oral lichen planus lesions. Anticancer Res. 26:357–362. 2006.PubMed/NCBI
24	Lei L, Tan WX, Zhou XL and Zheng PE: Expression of Fas and Fas ligand in infiltrating lymphocytes in patients with oral lichen planus. Zhonghua Kou Qiang Yi Xue Za Zhi. 45:219–222. 2010.(In Chinese).
25	Santoro A, Majorana A, Bardellini E, Festa S, Sapelli P and Facchetti F: NF-kappaB expression in oral and cutaneous lichen planus. J Pathol. 201:466–472. 2003. View Article : Google Scholar : PubMed/NCBI
26	Lei L, Yu M, Gao XY, Zhou XL and Zhan LH: Expression of TGF-beta receptors in CD8+T cells of oral lichen planus. Zhonghua Kou Qiang Yi Xue Za Zhi. 43:99–100. 2008.(In Chinese).
27	Apostolou I, Sarukhan A, Klein L and von Boehmer H: Origin of regulatory T cells with known specificity for antigen. Nat Immunol. 3:756–763. 2002.PubMed/NCBI
28	Wildin RS, Ramsdell F, Peake J, et al: X-linked neonatal diabetes mellitus, enteropathy and endocrinopathy syndrome is the human equivalent of mouse scurfy. Nat Genet. 27:18–20. 2001. View Article : Google Scholar : PubMed/NCBI
29	Lourenço EV and La Cava A: Natural regulatory T cells in autoimmunity. Autoimmunity. 44:33–42. 2011.
30	Tao XA, Xia J, Chen XB, et al: Foxp3 T regulatory cells in lesions of oral lichen planus correlated with disease activity. Oral Dis. 16:76–82. 2010. View Article : Google Scholar : PubMed/NCBI
31	Vargas-Rojas MI, Crispín JC, Richaud-Patin Y and Alcocer-Varela J: Quantitative and qualitative normal regulatory T cells are not capable of inducing suppression in SLE patients due to T-cell resistance. Lupus. 17:289–294. 2008. View Article : Google Scholar : PubMed/NCBI
32	Beavis PA, Gregory B, Green P, et al: Resistance to regulatory T cell-mediated suppression in rheumatoid arthritis can be bypassed by ectopic foxp3 expression in pathogenic synovial T cells. Proc Natl Acad Sci USA. 108:16717–16722. 2011. View Article : Google Scholar : PubMed/NCBI
33	Buckner JH: Mechanisms of impaired regulation by CD4(+)CD25(+)FOXP3(+) regulatory T cells in human autoimmune diseases. Nat Rev Immunol. 10:849–859. 2010.
34	Jungell P, Malmström M, Wartiovaara J, Konttinen Y and Sane J: Ultrastructure of oral leukoplakia and lichen planus I. Basal region and inflammatory cells. J Oral Pathol. 16:170–178. 1987. View Article : Google Scholar : PubMed/NCBI
35	Brant JMC, Vasconcelos AC and Rodrigues LV: Role of apoptosis in erosive and reticular oral lichen planus exhibiting variable epithelial thickness. Braz Dent J. 19:179–185. 2008.PubMed/NCBI
36	Karatsaidis A, Schreurs O, Helgeland K, Axéll T and Schenck K: Erythematous and reticular forms of oral lichen planus and oral lichenoid reactions differ in pathological features related to disease activity. J Oral Pathol Med. 32:275–281. 2003. View Article : Google Scholar : PubMed/NCBI
37	Wan YY and Flavell RA: The roles for cytokines in the generation and maintenance of regulatory T cells. Immunological Rev. 212:114–130. 2006. View Article : Google Scholar : PubMed/NCBI
38	van Amelsfort JM, van Roon JA, Noordegraaf M, et al: Proinflammatory mediator-induced reversal of CD4+, CD25+ regulatory T cell-mediated suppression in rheumatoid arthritis. Arthritis Rheum. 56:732–742. 2007.PubMed/NCBI
39	Simark-Mattsson C, Bergenholtz G, Jontell M, et al: Distribution of interleukin-2, -4, -10, tumour necrosis factor-alpha and transforming growth factor-beta mRNAs in oral lichen planus. Arch Oral Biol. 44:499–507. 1999. View Article : Google Scholar : PubMed/NCBI
40	Prime SS, Pring M, Davies M and Paterson IC: TGF-beta signal transduction in oro-facial health and non-malignant disease (part I). Crit Rev Oral Biol Med. 15:324–336. 2004. View Article : Google Scholar : PubMed/NCBI
41	Valencia X, Stephens G, Goldbach-Mansky R, Wilson M, Shevach EM and Lipsky PE: TNF downmodulates the function of human CD4+CD25hi T-regulatory cells. Blood. 108:253–261. 2006.
42	O’Sullivan BJ, Thomas HE, Pai S, et al: IL-1 beta breaks tolerance through expansion of CD25+ effector T cells. J Immunol. 176:7278–7287. 2006.PubMed/NCBI
43	Wan S, Xia C and Morel L: IL-6 produced by dendritic cells from lupus-prone mice inhibits CD4⁺CD25⁺ T cell regulatory functions. J Immunol. 178:271–279. 2007. View Article : Google Scholar : PubMed/NCBI
44	Marie JC, Letterio JJ, Gavin M and Rudensky AY: TGF-beta1 maintains suppressor function and Foxp3 expression in CD4⁺CD25⁺ regulatory T cells. J Exp Med. 201:1061–1067. 2005. View Article : Google Scholar : PubMed/NCBI
45	Wan YY and Flavell RA: Regulatory T-cell functions are subverted and converted owing to attenuated Foxp3 expression. Nature. 445:766–770. 2007. View Article : Google Scholar : PubMed/NCBI
46	Williams LM and Rudensky AY: Maintenance of the Foxp3-dependent developmental program in mature regulatory T cells requires continued expression of Foxp3. Nat Immunol. 8:277–284. 2007. View Article : Google Scholar : PubMed/NCBI
47	Frisullo G, Nociti V, Iorio R, et al: Regulatory T cells fail to suppress CD4T+-bet+ T cells in relapsing multiple sclerosis patients. Immunology. 127:418–428. 2009.PubMed/NCBI