• 1.

    WHO, 2017. Global leprosy update, 2016: accelerating reduction of disease burden. Wkly Epidemiol Rec 92: 501519.

  • 2.

    Talhari C, Talhari S, Penna GO, 2015. Clinical aspects of leprosy. Clin Dermatol 33: 2637.

  • 3.

    Cardoso CC, Pereira AC, de Sales Marques C, Moraes MO, 2011. Leprosy susceptibility: genetic variations regulate innate and adaptive immunity, and disease outcome. Future Microbiol 6: 533549.

    • Search Google Scholar
    • Export Citation
  • 4.

    Ridley DS, Jopling WH, 1966. Classification of leprosy according to immunity. A five-group system. Int J Lepr Other Mycobact Dis 34: 255273.

    • Search Google Scholar
    • Export Citation
  • 5.

    Massone C, Belachew WA, Schettini A, 2015. Histopathology of the lepromatous skin biopsy. Clin Dermatol. 33: 3845.

  • 6.

    Nath I, Saini C, Valluri VL, 2015. Immunology of leprosy and diagnostic challenges. Clin Dermatol. 33: 9098.

  • 7.

    Nery JA, Vieira LM, de Matos HJ, Gallo ME, Sarno EM, 1998. Reactional states in multibacillary Hansen disease patients during multidrug therapy. Rev Inst Med Trop Sao Paulo 40: 363370.

    • Search Google Scholar
    • Export Citation
  • 8.

    Dos Santos LN, da Silva PH, Alvim IM, Nery JA, Lara FA, Sarno EN, Esquenazi D, 2016. Role of TEFFECTOR/MEMORY cells, TBX21 gene expression and T-cell homing receptor on type 1 reaction in borderline lepromatous leprosy patients. PLoS One 11: e0164543.

    • Search Google Scholar
    • Export Citation
  • 9.

    Pocaterra L, Jain S, Reddy R, Muzaffarullah S, Torres O, Suneetha S, Lockwood DN, 2006. Clinical course of erythema nodosum leprosum: an 11-year cohort study in Hyderabad, India. Am J Trop Med Hyg 74: 868879.

    • Search Google Scholar
    • Export Citation
  • 10.

    Kahawita IP, Lockwood DNJ, 2008. Towards understanding the pathology of erythema nodosum leprosum. Trans R Soc Trop Med Hyg 102: 329337.

  • 11.

    Wemambu SN, Turk JL, Waters MF, Rees RJ, 1969. Erythema nodosum leprosum: a clinical manifestation of the arthus phenomenon. Lancet 2: 933935.

  • 12.

    Modlin RL, Bakke AC, Vaccaro SA, Horwitz DA, Taylor CR, Rea TH, 1985. Tissue and blood T-lymphocyte subpopulations in erythema nodosum leprosum. Arch Dermatol 121: 216219.

    • Search Google Scholar
    • Export Citation
  • 13.

    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 9: 7583.

    • Search Google Scholar
    • Export Citation
  • 14.

    Sallusto F, Lenig D, Forster R, Lipp M, Lanzavecchia A, 1999. Two subsets of memory T lymphocytes with distinct homing potentials and effector functions. Nature 401: 708712.

    • Search Google Scholar
    • Export Citation
  • 15.

    Murphy KM, Stockinger B, 2010. Effector T cell plasticity: flexibility in the face of changing circumstances. Nat Immunol 11: 674680.

  • 16.

    Silva DSD et al. 2018. Blood coagulation abnormalities in multibacillary leprosy patients. PLoS Negl Trop Dis 12: e0006214.

  • 17.

    Bryceson ADM, Pfaltzgraff RE, 1990. Leprosy, 3rd edition. Edinburgh, London, Melbourne and New York: Churchill Livingstone, 240 pp.

  • 18.

    Manandhar R, LeMaster JW, Roche PW, 1999. Risk factors for erythema nodosum leprosum. Int J Lepr Other Mycobact Dis 67: 270278.

  • 19.

    Voorend CG, Post EB, 2013. A systematic review on the epidemiological data of erythema nodosum leprosum, a type 2 leprosy reaction. PLoS Negl Trop Dis 7: e2440.

    • Search Google Scholar
    • Export Citation
  • 20.

    Mattos KA, Lara FA, Oliveira VG, Rodrigues LS, D’Avila H, Melo RC, Manso PP, Sarno EN, Bozza PT, Pessolani MC, 2011. Modulation of lipid droplets by Mycobacterium leprae in Schwann cells: a putative mechanism for host lipid acquisition and bacterial survival in phagosomes. Cell Microbiol 13: 259273.

    • Search Google Scholar
    • Export Citation
  • 21.

    Axelsson-Robertson R, Rao M, Loxton AG, Walzl G, Bates M, Zumla A, Maeurer M, 2015. Frequency of Mycobacterium tuberculosis-specific CD8+ T-cells in the course of anti-tuberculosis treatment. Int J Infect Dis 32: 2329.

    • Search Google Scholar
    • Export Citation
  • 22.

    Caccamo N et al. 2009. Analysis of Mycobacterium tuberculosis-specific CD8 T-cells in patients with active tuberculosis and in individuals with latent infection. PLoS One 4: e5528.

    • Search Google Scholar
    • Export Citation
  • 23.

    Khamesipour A, Nateghi Rostami M, Tasbihi M, Miramin Mohammadi A, Shahrestani T, Sarrafnejad A, Sohrabi Y, Eskandari SE, Keshavarz Valian H, 2012. Phenotyping of circulating CD8+ T cell subsets in human cutaneous leishmaniasis. Microbes Infect 14: 702711.

    • Search Google Scholar
    • Export Citation
  • 24.

    Negera E, Bobosha K, Walker SL, Endale B, Howe R, Aseffa A, Dockrell HM, Lockwood DN, 2017. New insight into the pathogenesis of erythema nodosum leprosum: the role of activated memory T-cells. Front Immunol 15: 1149.

    • Search Google Scholar
    • Export Citation
  • 25.

    Surh CD, Boyman O, Purton JF, Sprent J, 2006. Homeostasis of memory T cells. Immunol Rev 211: 154163.

  • 26.

    Terrazzini N, Mantegani P, Kern F, Fortis C, Mondino A, Caserta S, 2018. Interleukin-7 unveils pathogen-specific T cells by enhancing antigen-recall responses. J Infect Dis 217: 19972007.

    • Search Google Scholar
    • Export Citation
  • 27.

    Gebhardt T, Wakim LM, Eidsmo L, Reading PC, Heath WR, Carbone FR, 2009. Memory T cells in nonlymphoid tissue that provide enhanced local immunity during infection with herpes simplex virus. Nat Immunol 10: 524530.

    • Search Google Scholar
    • Export Citation
  • 28.

    Pham D, Vincentz JW, Firulli AB, Kaplan MH, 2012. Twist1 regulates Ifng expression in Th1 cells by interfering with Runx3 function. J Immunol 189: 832840.

    • Search Google Scholar
    • Export Citation
  • 29.

    Sakaguchi S, Miyara M, Costantino CM, Hafler DA, 2010. FOXP3+ regulatory T cells in the human immune system. Nat Rev Immunol 10: 490500.

  • 30.

    Roncarolo MG, Gregori S, Battaglia M, Bacchetta R, Fleischhauer K, Levings MK, 2006. Interleukin-10-secreting type 1 regulatory T cells in rodents and humans. Immunol Rev 212: 2850.

    • Search Google Scholar
    • Export Citation
  • 31.

    Chevalier MF, Didier C, Petitjean G, Karmochkine M, Girard PM, Barré-Sinoussi F, Scott-Algara D, Weiss L, 2015. Phenotype alterations in regulatory T-cell subsets in primary HIV infection and identification of Tr1-like cells as the main interleukin 10-producing CD4+ T cells. J Infect Dis 211: 769779.

    • Search Google Scholar
    • Export Citation
  • 32.

    Sarno EN, Grau GE, Vieira LM, Nery JA, 1991. Serum levels of tumour necrosis factor-alpha and interleukin-1 beta during leprosy reactional states. Clin Exp Immunol 84: 103108.

    • Search Google Scholar
    • Export Citation
  • 33.

    Teles RM, Moraes MO, Geraldo NT, Salles AM, Sarno EN, Sampaio EP, 2002. Differential TNFalpha mRNA regulation detected in the epidermis of leprosy patients. Arch Dermatol Res 294: 355362.

    • Search Google Scholar
    • Export Citation
  • 34.

    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 Dis 5: e1327.

    • Search Google Scholar
    • Export Citation
  • 35.

    Hussain R, Lucas SB, Kifayet A, Jamil S, Raynes J, Uqaili Z, Dockrell HM, Chiang TJ, McAdam KP, 1995. Clinical and histological discrepancies in diagnosis of ENL reactions classified by assessment of acute phase proteins SAA and CRP. Int J Lepr Other Mycobact Dis 63: 222230.

    • Search Google Scholar
    • Export Citation
  • 36.

    Foss NT, de Oliveira EB, Silva CL, 1993. Correlation between TNF production, increase of plasma C-reactive protein level and suppression of T lymphocyte response to concanavalin A during erythema nodosum leprosum. Int J Lepr Other Mycobact Dis 61: 218226.

    • Search Google Scholar
    • Export Citation
  • 37.

    Evans HG et al. 2014. TNF-α blockade induces IL-10 expression in human CD4+ T cells. Nat Commun 5: 3199.

  • 38.

    Esquenazi D, Alvim IM, Pinheiro RO, Oliveira EB, Moreira LO, Sarno EN, Nery JA, 2015. Correlation between central memory T cell expression and proinflammatory cytokine production with clinical presentation of multibacillary leprosy relapse. PLoS One 10: e0127416.

    • Search Google Scholar
    • Export Citation
  • 39.

    Farber DL, Yudanin NA, Restifo NP, 2014. Human memory T cells: generation, compartmentalization and homeostasis. Nat Rev Immunol 14: 2435.

  • 40.

    Park CO, Kupper TS, 2015. The emerging role of resident memory T cells in protective immunity and inflammatory disease. Nat Med 21: 688697.

    • Search Google Scholar
    • Export Citation
  • 41.

    Stirling DP, Koochesfahani KM, Steeves JD, Tetzlaff W, 2005. Minocycline as a neuroprotective agent. Neuroscientist 11: 308322.

  • 42.

    El-Khalawany M, Shaaban D, Sultan M, Abd Alsalam F, 2012. Inhibition of angiogenesis as a new therapeutic target in the treatment of lepromatous leprosy. Clin Cosmet Investig Dermatol 5: 16.

    • Search Google Scholar
    • Export Citation
  • 43.

    Garrido-Mesa N, Zarzuelo A, Gálvez J, 2013. Minocycline: far beyond an antibiotic. Br J Pharmacol 169: 337352.

 
 
 

 

 
 
 

 

 

 

 

 

 

Involvement of TNF-Producing CD8+ Effector Memory T Cells with Immunopathogenesis of Erythema Nodosum Leprosum in Leprosy Patients

View More View Less
  • 1 Leprosy Laboratory, Oswaldo Cruz Institute, Oswaldo Cruz Foundation, Rio de Janeiro, Brazil;
  • | 2 Department of Pathology and Laboratories, School of Medical Sciences, State University of Rio de Janeiro, Rio de Janeiro, Brazil

Type 2 reaction (T2R) or erythema nodosum leprosum (ENL), a sudden episode of acute inflammation predominantly affecting lepromatous leprosy patients (LL), characterized by a reduced cellular immune response. This possibly indicates a close relationship between the onset of T2R and the altered frequency, and functional activity of T lymphocytes, particularly of memory subsets. This study performed ex vivo and in vitro characterizations of T cell blood subpopulations from LL patients with or without T2R. In addition, the evaluation of activity of these subpopulations was performed by analyzing the frequency of these cells producing IFN-γ, TNF, and IL-10 by flow cytometry. Furthermore, the expression of transcription factors, for the differentiation of T cells, were analyzed by quantitative real-time polymerase chain reaction. Our results showed an increased frequency of CD8+/TNF+ effector memory T cells (TEM) among T2Rs. Moreover, there was evidence of a reduced frequency of CD4 and CD8+ IFN-γ–producing cells in T2R, and a reduced expression of STAT4 and TBX21. Finally, a significant and positive correlation between bacteriological index (BI) of T2R patients and CD4+/TNF+ and CD4+/IFN-γ+ T cells was observed. Thus, negative correlation between BI and the frequency of CD4+/IL-10+ T cells was noted. These results suggest that CD8+/TNF+ TEM are primarily responsible for the transient alteration in the immune response to Mycobacterium leprae in ENL patients. Thus, our study improves our understanding of pathogenic mechanisms and might suggest new therapeutic approaches for leprosy.

    • Supplemental Materials (PDF 120 KB)

Author Notes

Address correspondence to Danuza Esquenazi, Leprosy Laboratory, Oswaldo Cruz Institute, Oswaldo Cruz Foundation, Ave. Brasil 4365, Manguinhos, Rio de Janeiro 21040-360, Brazil. E-mail: danuza@ioc.fiocruz.br

Financial support: P. H. L. S. and L. N. S. are a postgraduate students sponsored by FIOCRUZ/CAPES (process number 16.11.38.106 and 16.06.38.047, respectively). E. N. S. is fellow sponsored by CNPq (process number 305885/2014-6). This investigation received financial support from the National Counsel of Technological and Scientific Development–CNPq (PAPES VI/Fiocruz, process number 407838/2012-0, under coordination by D. E.).

Authors’ addresses: Pedro Henrique L. Silva, Luciana N. Santos, Mayara A. Mendes, José A. C. Nery, and Euzenir N. Sarno, Leprosy Laboratory, Oswaldo Cruz Institute, Oswaldo Cruz Foundation, Rio de Janeiro, Brazil, E-mails: peddro.henrique10@gmail.com, lu.nahar@gmail.com, mayarah.rj@gmail.com, neryjac@gmail.com, and euzenir@fiocruz.br. Danuza Esquenazi, Leprosy Laboratory, Oswaldo Cruz Institute, Oswaldo Cruz Foundation, Rio de Janeiro, Brazil, and Department of Pathology and Laboratories, School of Medical Sciences, State University of Rio de Janeiro, Rio de Janeiro, Brazil, E-mail: danuza@ioc.fiocruz.br.

These authors contributed equally to this work.

Save