1921
Volume 94, Issue 4
  • ISSN: 0002-9637
  • E-ISSN: 1476-1645

Abstract

Abstract

Leprosy is frequently complicated by the appearance of reactions that are difficult to treat and are the main cause of sequelae. We speculated that disturbances in regulatory T-cells (Tregs) could play a role in leprosy reactions. We determined the frequency of circulating Tregs in patients with type 1 reaction (T1R) and type 2 reaction (T2R). The in situ frequency of Tregs and interleukin (IL)-17, IL-6, and transforming growth factor beta (TGF)-β-expressing cells was also determined. T2R patients showed markedly lower number of circulating and in situ Tregs than T1R patients and controls. This decrease was paralleled by increased in situ IL-17 expression but decreased TGF-β expression. Biopsies from T1R and T2R patients before the reaction episodes showed similar number of forkhead box protein P3+ (FoxP3+) and IL-17+ cells. However, in biopsies taken during the reaction, T2R patients showed a decrease in Tregs and increase in IL-17+ cells, whereas T1R patients showed the opposite: Tregs increased but IL-17+ cells decreased. We also found decreased expansion of Tregs upon in vitro stimulation with and a trend for lower expression of FoxP3 and the immunosuppressive molecule cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) in T2R Tregs. Our results provide some evidence to the hypothesis that, in T2R, downmodulation of Tregs may favor the development of T-helper-17 responses that characterize this reaction.

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References

  1. Kahawita IP, Walker SL, Lockwood DL, , 2008. Leprosy type 1 reactions and erythema nodosum leprosum. An Bras Dermatol 83: 7582.[Crossref] [Google Scholar]
  2. Walker SL, Lockwood DN, , 2008. Leprosy type 1 (reversal) reactions and their management. Lepr Rev 79: 372386. [Google Scholar]
  3. Kahawita IP, Lockwood DNJ, , 2008. Towards understanding the pathology of erythema nodosum leprosum. Trans R Soc Trop Med Hyg 102: 329337.[Crossref] [Google Scholar]
  4. Pandhi D, Chhabra N, , 2013. New insights in the pathogenesis of type 1 and type 2 lepra reaction. Indian J Dermatol Venereol Leprol 79: 739749.[Crossref] [Google Scholar]
  5. Scollard DM, Martelli CMT, Stefani MMA, Maroja MF, Villahermosa L, Pardillo F, Tamang KB, , 2015. Risk factors for leprosy reactions in three endemic countries. Am J Trop Med Hyg 92: 108114.[Crossref] [Google Scholar]
  6. Saunderson P, Gebre S, Byass P, , 2000. Reversal reactions in the skin lesions of AMFES patients: incidence and risk factors. Lepr Rev 71: 309317. [Google Scholar]
  7. Saporta L, Yuksel A, , 1994. Androgenic status in patients with lepromatous leprosy. Br J Urol 74: 221224.[Crossref] [Google Scholar]
  8. Misch EA, Macdonald M, Ranjit C, Sapkota BR, Wells RD, Siddiqui MR, Kaplan G, Hawn TR, , 2008. Human TLR1 deficiency is associated with impaired mycobacterial signaling and protection from leprosy reversal reaction. PLoS Negl Trop Dis 2: e231.[Crossref] [Google Scholar]
  9. Bochud PY, Hawn TR, Siddiqui MR, Saunderson P, Britton S, Abraham I, Argaw AT, Janer M, Zhao LP, Kaplan G, Aderem A, , 2008. Toll-like receptor 2 (TLR2) polymorphisms are associated with reversal reaction in leprosy. J Infect Dis 197: 253261.[Crossref] [Google Scholar]
  10. Sapkota BR, Macdonald M, Berrington WR, Misch EA, Ranjit C, Siddiqui MR, Kaplan G, Hawn TR, , 2011. Association of TNF, MBL, and VDR polymorphisms with leprosy phenotypes. Hum Immunol 10: 992998. [Google Scholar]
  11. Berrington WR, Macdonald M, Khadge S, Sapkota BR, Janer M, Hagge DA, Kaplan G, Hawn TR, , 2010. Common polymorphisms in the NOD2 gene region are associated with leprosy and its reactive states. J Infect Dis 201: 14221435.[Crossref] [Google Scholar]
  12. Sakaguchi S, Yamaguchi T, Nomura T, Ono M, , 2008. Regulatory T cells and immune tolerance. Cell 133: 775787.[Crossref] [Google Scholar]
  13. Hori S, Nomura T, Sakaguchi S, , 2003. Control of regulatory T cell development by the transcription factor Foxp3. Science 299: 10571061.[Crossref] [Google Scholar]
  14. Palermo ML, Pagliari C, Trindade MA, Yamashitafuji TM, Duarte AJ, Cacere CR, Benard G, , 2012. Increased expression of regulatory T cells and down-regulatory molecules in lepromatous leprosy. Am J Trop Med Hyg 86: 878883.[Crossref] [Google Scholar]
  15. Saini C, Ramesh V, Nath I, , 2014. Increase in TGF-β secreting CD4+ CD25+ FOXP3+ T regulatory cells in anergic lepromatous leprosy patients. PLoS Negl Trop Dis 8: e2639.[Crossref] [Google Scholar]
  16. Kumar S, Naqvi RA, Ali R, Rani R, Khanna N, Rao DN, , 2013. CD4+CD25+ T regs with acetylated FoxP3 are associated with immune suppression in human leprosy. Mol Immunol 56: 513520.[Crossref] [Google Scholar]
  17. Quaresma JA, Esteves PC, de Sousa Aarão TL, de Sousa JR, da Silva Pinto D, Fuzii HT, , 2014. Apoptotic activity and Treg cells in tissue lesions of patients with leprosy. Microb Pathog 76: 8488.[Crossref] [Google Scholar]
  18. Bobosha K, Wilson L, van Meijgaarden KE, Bekele Y, Zewdie M, Schip JJ, Abebe M, Hussein J, Khadge S, Neupane KD, Hagge DA, Jordanova ES, Aseffa A, Ottenhoff TH, Geluk A, , 2014. T-cell regulation in lepromatous leprosy. PLoS Negl Trop Dis 8: e2773.[Crossref] [Google Scholar]
  19. Ridley DS, Jopling WH, , 1966. Classification of leprosy according to immunity. A five-group system. Int J Lepr Other Mycobact Dis 34: 255273. [Google Scholar]
  20. Biancotto A, Dagur PK, Fuchs JC, Langweiler M, McCoy JP, Jr, 2012. OMIP-004: in-depth characterization of human T regulatory cells. Cytometry A 81: 1516.[Crossref] [Google Scholar]
  21. Fernandes C, Gonçalves HS, Cabral PB, Pinto HC, Pinto MIM, Câmara LMC, , 2013. Increased frequency of CD4 and CD8 regulatory T cells in individuals under 15 years with multibacillary leprosy. PLoS One 8: e79072.[Crossref] [Google Scholar]
  22. Vukmanovic-Stejic M, Agius E, Booth N, Dunne PJ, Lacy KE, Reed JR, Sobande TO, Kissane S, Salmon M, Rustin MH, Akbar AN, , 2008. The kinetics of CD4+Foxp3+ T cell accumulation during a human cutaneous antigen-specific memory response in vivo. J Clin Invest 118: 36393650.[Crossref] [Google Scholar]
  23. Vukmanovic-Stejic M, Sandhu D, Sobande TO, Agius E, Lacy KE, Riddell N, Montez S, Dintwe OB, Scriba TJ, Breuer J, Nikolich-Zugich J, Ogg G, Rustin MH, Akbar AN, , 2013. Varicella zoster-specific CD4+ Foxp3+ T cells accumulate after cutaneous antigen challenge in humans. J Immunol 190: 977986.[Crossref] [Google Scholar]
  24. Noack M, Miossec P, , 2014. Th17 and regulatory T cell balance in autoimmune and inflammatory diseases. Autoimmun Rev 13: 668667.[Crossref] [Google Scholar]
  25. Ouyang W, Kolls JK, Zheng Y, , 2008. The biological functions of T helper 17 cell effector cytokines in inflammation. Immunity 28: 454467.[Crossref] [Google Scholar]
  26. Stefani MM, Guerra JG, Sousa AL, Costa MB, Oliveira ML, Martelli CT, Scollard DM, , 2009. Potential plasma markers of type 1 and type 2 leprosy reactions: a preliminary report. BMC Infect Dis 27: 975. [Google Scholar]
  27. Sousa AL, Fava VM, Sampaio LH, Martelli CM, Costa MB, Mira MT, Stefani MM, , 2012. Genetic and immunological evidence implicates interleukin 6 as a susceptibility gene for leprosy type 2 reaction. J Infect Dis 205: 14171424.[Crossref] [Google Scholar]
  28. Chaitanya VS, Lavania M, Nigam A, Turankar RP, Singh I, Horo I, Sengupta U, Jadhav RS, , 2013. Cortisol and proinflammatory cytokine profiles in type 1 (reversal) reactions of leprosy. Immunol Lett 156: 159167.[Crossref] [Google Scholar]
  29. Belgaumkar VA, Gokhale NR, Mahajan PM, Bharadwaj R, Pandit DP, Deshpande S, , 2007. Circulating cytokine profiles in leprosy patients. Lepr Rev 78: 223230. [Google Scholar]
  30. Iyer A, Hatta M, Usman R, Luiten S, Oskam L, Faber W, Geluk A, Das P, , 2007. Serum levels of interferon-gamma, tumour necrosis factor-alpha, soluble interleukin-6R and soluble cell activation markers for monitoring response to treatment of leprosy reactions. Clin Exp Immunol 150: 210216.[Crossref] [Google Scholar]
  31. Moraes MO, Sarno EN, Teles RMB, Almeida AS, Saraiva BC, Nery JAC, Sampaio EP, , 2000. Anti-inflammatory drugs block cytokine mRNA accumulation in the skin and improve the clinical condition of reactional leprosy patients. J Invest Dermatol 115: 935941.[Crossref] [Google Scholar]
  32. Atkinson SE, Khanolkar-Young S, Marlowe S, Jain S, Reddy RG, Suneetha S, Lockwood DN, , 2004. Detection of IL-13, IL-10, and IL-6 in the leprosy skin lesions of patients during prednisolone treatment for type 1 (T1R) reactions. Int J Lepr Other Mycobact Dis 72: 2734.[Crossref] [Google Scholar]
  33. Teles RM, Moraes MO, Geraldo NT, Salles AM, Sarno EN, Sampaio EP, , 2002. Differential TNF-alpha mRNA regulation detected in the epidermis of leprosy patients. Arch Dermatol Res 294: 355362. [Google Scholar]
  34. Martiniuk F, Giovinazzo J, Tan AU, Shahidullah R, Haslett P, Kaplan G, Levis WR, , 2012. Lessons of leprosy: the emergence of TH17 cytokines during type II reactions (ENL) is teaching us about T-cell plasticity. J Drugs Dermatol 11: 626630. [Google Scholar]
  35. Goodman WA, Levine AD, Massari JV, Sugiyama H, McCormick TS, Cooper KD, , 2009. IL-6 signaling in psoriasis prevents immune suppression by regulatory T cells. J Immunol 183: 31703176.[Crossref] [Google Scholar]
  36. Fujimoto M, Nakano M, Terabe F, Kawahata H, Ohkawara T, Han Y, Ripley B, Serada S, Nishikawa T, Kimura A, Nomura S, Kishimoto T, Naka T, , 2011. The influence of excessive IL-6 production in vivo on the development and function of Foxp3+ regulatory T cells. J Immunol 186: 3240.[Crossref] [Google Scholar]
  37. Walunas TL, Lenschow DJ, Bakker CY, Linsley OS, Freeman GJ, Green JM, Thompson CB, Bluestone JA, , 1994. CTLA-4 can function as a negative regulator of T-cell activation. Immunity 1: 405413.[Crossref] [Google Scholar]
  38. Borsellino G, Kleinewietfeld M, Di Mitri D, Sternjak A, Diamantini A, Giometto R, Höpner S, Centonze D, Bernardi G, Dell'Acqua ML, Rossini PM, Battistini L, Rötzschke O, Falk K, , 2007. Expression of ectonucleotidase CD39 by Foxp3+ Treg cells: hydrolysis of extracellular ATP and immune suppression. Blood 110: 12251232.[Crossref] [Google Scholar]
  39. Lawrence DA, , 2001. Latent-TGF-beta: an overview. Mol Cell Biochem 219: 163170.[Crossref] [Google Scholar]
  40. Chauhan SK, Saban DR, Lee HK, Dana R, , 2009. Levels of Foxp3 in regulatory T cells reflect their functional status in transplantation. J Immunol 182: 148153.[Crossref] [Google Scholar]
  41. Pulte ED, Broekman MJ, Olson KE, Drosopoulos JHF, Kizer JR, Islam N, Marcus AJ, , 2007. CD39/NTPDase-1 activity and expression in normal leukocytes. Thromb Res 121: 309317.[Crossref] [Google Scholar]
  42. Lockwood DN, Suneetha L, Sagili KD, Chaduvula MV, Mohammed I, van Brakel W, Smith WC, Nicholls P, Suneetha S, , 2011. Cytokine and protein markers of leprosy reactions in skin and nerves: baseline results for the North Indian INFIR cohort. PLoS Negl Trop 5: e1327.[Crossref] [Google Scholar]
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Supplementary PDF

  • Received : 14 Sep 2015
  • Accepted : 28 Dec 2015
  • Published online : 06 Apr 2016

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