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Clinical Oral Investigations

, Volume 18, Issue 8, pp 1903–1911 | Cite as

Hydroxychloroquine decreases the upregulated frequencies of Tregs in patients with oral lichen planus

  • Yanan Zhu
  • Jingjing Li
  • Yang Bai
  • Xiang Wang
  • Ning Duan
  • Hongliu Jiang
  • Tingting WangEmail author
  • Wenmei WangEmail author
Original Article

Abstract

Objective

Regulatory T cells (Tregs) have emerged as important mediators in inflammatory and autoimmune diseases. We investigated the possible involvement of Tregs in oral lichen planus (OLP) and the influence of clinical therapy (hydroxychloroquine and prednisone) on the frequencies of Tregs in OLP patients.

Materials and methods

One hundred fifty patients diagnosed with OLP were the study cohort. Levels of Tregs in blood and tissues were detected using flow cytometry and immunostaining, respectively. Cytokine production was assessed using a proteome profiler array and determined by enzyme-linked immunosorbent assay. mRNA expression of transcription factors was detected by real-time quantitative PCR. Hydroxychloroquine or prednisone was used to treat patients randomly. The frequency of Tregs was detected before treatment and 2 weeks after treatment.

Results

Compared with healthy volunteers, OLP patients had a higher proportion of Tregs in serum and tissues before treatment (P < 0.001). Serum concentrations of interleukin (IL)-8, transforming growth factor (TGF)-β1, and IL-10 were significantly higher in patients than those in healthy controls. mRNA expression of Treg-related genes, including TGF-β, IL-10, signal transducer and activator of transcription 6, and GATA binding protein 3, were upregulated significantly in OLP patients. The frequency of Tregs was downregulated after hydroxychloroquine treatment.

Conclusions

These results suggest that Tregs may contribute to the immunopathogenesis of OLP and may provide a new therapeutic target for OLP treatment.

Clinical relevance

T cell-mediated immune dysfunction may have a crucial role in OLP development. However, T helper 1 (Th1)/Th2 imbalance does not appear to be sufficient to understand the pathogenesis of OLP. This is the first study to show that Tregs are involved in the immunopathogenesis of OLP.

Keywords

Tregs Oral lichen planus Cytokine Hydroxychloroquine Prednisone 

Notes

Acknowledgments

This research was supported by grants from the National Natural Scientific Foundation of China (numbers 81070839 and 81101552), Key Project supported by the Medical Science and Technology Development Foundation, Nanjing Department of Health (ZKX10030), Jiangsu Province’s Outstanding Medical Academic Leader program (LJ201110), Natural Science Foundation of Jiangsu Province (BK2011571), and Specialized Research Fund for the Doctoral Program of Higher Education (20100091120002).

Conflict of interest

The authors declare that they have no conflict of interest.

References

  1. 1.
    Roopashree MR, Gondhalekar RV, Shashikanth MC, George J, Thippeswamy SH, Shukla A (2010) Pathogenesis of oral lichen planus—a review. J Oral Pathol Med 39:729–734PubMedCrossRefGoogle Scholar
  2. 2.
    Zhou ZT, Wei BJ, Shi P (2008) Osteopontin expression in oral lichen planus. J Oral Pathol Med 37:94–98PubMedCrossRefGoogle Scholar
  3. 3.
    Cortes-Ramirez DA, Gainza-Cirauqui ML, Echebarria-Goikouria MA, Aguirre-Urizar JM (2009) Oral lichenoid disease as a premalignant condition: the controversies and the unknown. Med Oral Patol Oral Cir Bucal 14:E118–E122PubMedGoogle Scholar
  4. 4.
    Torrente-Castells E, Figueiredo R, Berini-Aytes L, Gay-Escoda C (2010) Clinical features of oral lichen planus. A retrospective study of 65 cases. Med Oral Patol Oral Cir Bucal 15:e685–e690PubMedCrossRefGoogle Scholar
  5. 5.
    Sugerman PB, Savage NW, Walsh LJ, Zhao ZZ, Zhou XJ, Khan A et al (2002) The pathogenesis of oral lichen planus. Crit Rev Oral Biol Med 13:350–365PubMedCrossRefGoogle Scholar
  6. 6.
    Khan A, Farah CS, Savage NW, Walsh LJ, Harbrow DJ, Sugerman PB (2003) Th1 cytokines in oral lichen planus. J Oral Pathol Med 32:77–83PubMedCrossRefGoogle Scholar
  7. 7.
    Rhodus NL, Cheng B, Ondrey F (2007) Th1/Th2 cytokine ratio in tissue transudates from patients with oral lichen planus. Mediators Inflamm 2007:19854PubMedCrossRefPubMedCentralGoogle Scholar
  8. 8.
    Bonelli M, von Dalwigk K, Savitskaya A, Smolen JS, Scheinecker C (2008) Foxp3 expression in CD4+ T cells of patients with systemic lupus erythematosus: a comparative phenotypic analysis. Ann Rheum Dis 67:664–671PubMedCrossRefGoogle Scholar
  9. 9.
    Zhang B, Zhang X, Tang FL, Zhu LP, Liu Y, Lipsky PE (2008) Clinical significance of increased CD4 + CD25-Foxp3+ T cells in patients with new-onset systemic lupus erythematosus. Ann Rheum Dis 67:1037–1040PubMedCrossRefGoogle Scholar
  10. 10.
    Ito Y, Adachi Y, Makino T, Higashiyama H, Fuchizawa T, Shimizu T et al (2009) Expansion of FOXP3-positive CD4 + CD25+ T cells associated with disease activity in atopic dermatitis. Ann Allergy Asthma Immunol 103:160–165PubMedCrossRefGoogle Scholar
  11. 11.
    Lee JH, Yu HH, Wang LC, Yang YH, Lin YT, Chiang BL (2007) The levels of CD4 + CD25+ regulatory T cells in paediatric patients with allergic rhinitis and bronchial asthma. Clin Exp Immunol 148:53–63PubMedCrossRefPubMedCentralGoogle Scholar
  12. 12.
    Sakaguchi S (2005) Naturally arising Foxp3-expressing CD25 + CD4+ regulatory T cells in immunological tolerance to self and non-self. Nat Immunol 6:345–352PubMedCrossRefGoogle Scholar
  13. 13.
    Tao XA, Xia J, Chen XB, Wang H, Dai YH, Rhodus NL et al (2010) FOXP3 T regulatory cells in lesions of oral lichen planus correlated with disease activity. Oral Dis 16:76–82PubMedCrossRefGoogle Scholar
  14. 14.
    Carbone M, Goss E, Carrozzo M, Castellano S, Conrotto D, Broccoletti R et al (2003) Systemic and topical corticosteroid treatment of oral lichen planus: a comparative study with long-term follow-up. J Oral Pathol Med 32:323–329PubMedCrossRefGoogle Scholar
  15. 15.
    Eisen D (1993) Hydroxychloroquine sulfate (Plaquenil) improves oral lichen planus: an open trial. J Am Acad Dermatol 28:609–612PubMedCrossRefGoogle Scholar
  16. 16.
    De Argila D, Gonzalo A, Pimentel J, Rovira I (1997) Isolated lichen planus of the lip successfully treated with chloroquine phosphate. Dermatology 195:284–285PubMedCrossRefGoogle Scholar
  17. 17.
    Rad M, Hashemipoor MA, Mojtahedi A, Zarei MR, Chamani G, Kakoei S et al (2009) Correlation between clinical and histopathologic diagnoses of oral lichen planus based on modified WHO diagnostic criteria. Oral Surg Oral Med Oral Pathol Oral Radiol Endod 107:796–800PubMedCrossRefGoogle Scholar
  18. 18.
    Mignogna MD, Fedele S, Lo Russo L, Lo Muzio L, Bucci E (2004) Immune activation and chronic inflammation as the cause of malignancy in oral lichen planus: is there any evidence ? Oral Oncol 40:120–130PubMedCrossRefGoogle Scholar
  19. 19.
    Ou LS, Goleva E, Hall C, Leung DY (2004) T regulatory cells in atopic dermatitis and subversion of their activity by superantigens. J Allergy Clin Immunol 113:756–763PubMedCrossRefGoogle Scholar
  20. 20.
    Yang J, Chu Y, Yang X, Gao D, Zhu L, Wan L et al (2009) Th17 and natural Treg cell population dynamics in systemic lupus erythematosus. Arthritis Rheum 60:1472–1483PubMedCrossRefGoogle Scholar
  21. 21.
    Pereira JS, Monteiro BV, Nonaka CF, Silveira EJ, Miguel MC (2012) FoxP3(+) T regulatory cells in oral lichen planus and its correlation with the distinct clinical appearance of the lesions. Int J Exp Pathol 93:287–294PubMedCrossRefPubMedCentralGoogle Scholar
  22. 22.
    Zhang X, Koldzic DN, Izikson L, Reddy J, Nazareno RF, Sakaguchi S et al (2004) IL-10 is involved in the suppression of experimental autoimmune encephalomyelitis by CD25 + CD4+ regulatory T cells. Int Immunol 16:249–256PubMedCrossRefGoogle Scholar
  23. 23.
    Annacker O, Pimenta-Araujo R, Burlen-Defranoux O, Barbosa TC, Cumano A, Bandeira A (2001) CD25+ CD4+ T cells regulate the expansion of peripheral CD4 T cells through the production of IL-10. J Immunol 166:3008–3018PubMedCrossRefGoogle Scholar
  24. 24.
    Sun A, Wang JT, Chia JS, Chiang CP (2005) Serum interleukin-8 level is a more sensitive marker than serum interleukin-6 level in monitoring the disease activity of oral lichen planus. Br J Dermatol 152:1187–1192PubMedCrossRefGoogle Scholar
  25. 25.
    Simark-Mattsson C, Bergenholtz G, Jontell M, Eklund C, Seymour GJ, Sugerman PB et al (1999) Distribution of interleukin-2, -4, -10, tumour necrosis factor-alpha and transforming growth factor-beta mRNAs in oral lichen planus. Arch Oral Biol 44:499–507PubMedCrossRefGoogle Scholar
  26. 26.
    Zhao ZZ, Savage NW, Sugerman PB, Walsh LJ (2002) Mast cell/T cell interactions in oral lichen planus. J Oral Pathol Med 31:189–195PubMedCrossRefGoogle Scholar
  27. 27.
    Lu R, Zhou G, Du G, Xu X, Yang J, Hu J (2011) Expression of T-bet and GATA-3 in peripheral blood mononuclear cells of patients with oral lichen planus. Arch Oral Biol 56:499–505PubMedCrossRefGoogle Scholar
  28. 28.
    Beyersdorf N, Gaupp S, Balbach K, Schmidt J, Toyka KV, Lin CH et al (2005) Selective targeting of regulatory T cells with CD28 superagonists allows effective therapy of experimental autoimmune encephalomyelitis. J Exp Med 202:445–455PubMedCrossRefPubMedCentralGoogle Scholar
  29. 29.
    Chai JG, Xue SA, Coe D, Addey C, Bartok I, Scott D et al (2005) Regulatory T cells, derived from naive CD4 + CD25− T cells by in vitro Foxp3 gene transfer, can induce transplantation tolerance. Transplantation 79:1310–1316PubMedCrossRefGoogle Scholar
  30. 30.
    Loser K, Hansen W, Apelt J, Balkow S, Buer J, Beissert S (2005) In vitro-generated regulatory T cells induced by Foxp3-retrovirus infection control murine contact allergy and systemic autoimmunity. Gene Ther 12:1294–1304PubMedCrossRefGoogle Scholar
  31. 31.
    Ephrem A, Chamat S, Miquel C, Fisson S, Mouthon L, Caligiuri G et al (2008) Expansion of CD4 + CD25+ regulatory T cells by intravenous immunoglobulin: a critical factor in controlling experimental autoimmune encephalomyelitis. Blood 111:715–722PubMedCrossRefGoogle Scholar
  32. 32.
    Radulovic S, Jacobson MR, Durham SR, Nouri-Aria KT (2008) Grass pollen immunotherapy induces Foxp3-expressing CD4+ CD25+ cells in the nasal mucosa. J Allergy Clin Immunol 121:1467–1472, 1472 e1461PubMedCrossRefGoogle Scholar
  33. 33.
    Lin SC, Chen KH, Lin CH, Kuo CC, Ling QD, Chan CH (2007) The quantitative analysis of peripheral blood FOXP3-expressing T cells in systemic lupus erythematosus and rheumatoid arthritis patients. Eur J Clin Invest 37:987–996PubMedCrossRefGoogle Scholar

Copyright information

© Springer-Verlag Berlin Heidelberg 2014

Authors and Affiliations

  • Yanan Zhu
    • 1
  • Jingjing Li
    • 2
  • Yang Bai
    • 2
  • Xiang Wang
    • 2
  • Ning Duan
    • 2
  • Hongliu Jiang
    • 2
  • Tingting Wang
    • 3
    Email author
  • Wenmei Wang
    • 2
    Email author
  1. 1.Endodontic Department, Institute and Hospital of StomatologyNanjing University Medical SchoolNanjingChina
  2. 2.Department of Oral Medicine, Institute and Hospital of StomatologyNanjing University Medical SchoolNanjingChina
  3. 3.Immunology LaboratoryMedical School of Nanjing UniversityNanjingChina

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