Journal of Clinical Immunology

, Volume 22, Issue 6, pp 345–352

Cytokine Polarization in Miliary and Pleural Tuberculosis

  • Surendra K. Sharma
  • Dipender K. Mitra
  • Arumugam Balamurugan
  • Ravindra M. Pandey
  • Narinder K. Mehra


Cytokines were measured in patients with pleural effusion and miliary tuberculosis (TB). Patients with pleural effusion had significantly higher interferon-gamma (IFN-γ) levels (P < 0.001) in their pleural fluid as compared to that of peripheral blood of the same patients, thus exhibiting localization of predominantly Th1-type immunity in the pleural fluid. On the contrary, patients with miliary TB had higher IFN-γ levels in the peripheral blood as compared to their bronchoalveolar lavage fluid. Moreover, the median IFN-γ : IL-4 ratio in the peripheral blood of miliary TB patients was two-fold higher as compared to bronchoalveolar lavage fluid, suggesting that the cytokine profile at the disease site is skewed toward a Th2-like bias. Further, flow cytometry data revealed a significantly higher (P < 0.001) percentage of CD4+ pleural fluid lymphocytes expressing IFN-γ, whereas in the miliary TB, a nine-fold higher percentage of lymphocytes in bronchoalveolar lavage fluid expressed IL-4 in comparison with their peripheral CD4 T cells. Our data indicate, respectively, a Th1-like and Th2-like response in tuberculous pleural effusion and miliary TB, suggesting that these clinical forms of extrapulmonary tuberculosis probably reflect the extreme ends of a Th1–Th2 spectrum of the disease.

Tuberculosis pleural effusion miliary tuberculosis cytokines 


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  1. 1.
    World Health Organization: Global Tuberculosis Control. WHO Report 2001. Geneva, Switzerland, WHO/CDS/TB/2001.287Google Scholar
  2. 2.
    Lucey DR, Clerici M, Shearer GM: Type 1 and type 2 cytokine dysregulation in human infectious, neoplastic and inflammatory diseases. Clin Microbiol Rev 9:532–562, 1996Google Scholar
  3. 3.
    Yamamuro M, Uyemura K, Deans RJ, Weinberg K, Rea TH, Bloom BR, Modlin RL: Defining protective responses to pathogens: Cytokine profiles in leprosy lesions. Science 254:277–279, 1991Google Scholar
  4. 4.
    Snider DE, Onorato M: Epidemiology. In Tuberculosis: Clinical Management and New Challenges, MD Rossman, RR MacGregor (eds). New York, McGraw-Hill, 1995, pp 3–17Google Scholar
  5. 5.
    Surcel HM, Troye-Blomberg M, Paulie S, Andersson G, Moreno C, Pasvol G, Ivanyi J: Th1/Th2 profiles in tuberculosis based on the proliferation and cytokine response of blood lymphocytes to mycobacterial antigens. Immunology 81:171–176, 1994Google Scholar
  6. 6.
    Zhang M, Lin Y, Iyer DV, Gong J, Abrams JS, Barnes PF: T-cell cytokine responses in human infection with M. tuberculosis. Infect Immun 63:3231–3234, 1995Google Scholar
  7. 7.
    Sanchez FO, Rodriguez JI, Agudelo G, Garcia LF: Immune responsiveness and lymphokine production in patients with tuberculosis and healthy controls. Infect Immun 62:5673–5678, 1994Google Scholar
  8. 8.
    Lin Y, Zhang M, Hofman FM, Gong J, Barnes PF: Absence of a prominent Th2 cytokine response in human tuberculosis. Infect Immun 64:1351–1356, 1996Google Scholar
  9. 9.
    Ottenhoff THM, Kumararatne D, Casanova JL: Novel human immunodeficiencies reveal the essential role of type-1 cytokines in immunity to intracellular bacteria. Immunol Today 19:491–494, 1998Google Scholar
  10. 10.
    Flynn JL, Chan J, Triebold KJ, Dalton DK, Stewart TA, Bloom BR: An essential role for interferon gamma in resistance to Mycobacterium tuberculosis infection. J Exp Med 178:2249–2254, 1993Google Scholar
  11. 11.
    Hernandez Pando R, Orozcoe H, Sampieri A, Pavon L, Velasquillo C, Larriva-Sahd J, Alcocer JM, Madrid MV: Correlation between the kinetics of Th1/Th2 cells and pathology in a murine model of experimental pulmonary tuberculosis. Immunology 89:26–33, 1996Google Scholar
  12. 12.
    Lukacs NW, Addison CL, Gauldie J, Graham F, Simpson K, Strieter RM, Warmington K, Chensue SW, Kunkel SL: Transgeneinduced production of IL-4 alters the development and collagen expression of T helper cell I-type pulmonary granulomas. J Immunol 158:4478–4484, 1997Google Scholar
  13. 13.
    Sharma SK, Mohan A, Pande JN, Prasad L, Gupta AK, Khilnani, GC. Clinical profile, laboratory characteristics and outcome in miliary tuberculosis. QJM 88:29–37, 1995Google Scholar
  14. 14.
    Sharma SK, Saha PK, Dixit Y, Siddaramaiah NH, Seth P, Pande JN: HIV Seropositivity among adult tuberculosis patients in Delhi. Indian J Chest Dis Allied Sci 42:157–160, 2000Google Scholar
  15. 15.
    Sharma SK, Pande JN, Singh YN, Verma K, Kathait SS, Khare S, Malaviya AN: Pulmonary function and immunological abnormalities in miliary tuberculosis. Am Rev Respir Dis 145:1167–1171, 1992Google Scholar
  16. 16.
    Mitra DK, De Rosa SC, Luke A, Balamurugan A, Khaitan BK, Tung J, Mehra NK, Terr AI, O'Garra A, Herzenberg LA, Roederer M: Differential representations of memory T cell subsets are characteristic of polarized immunity in leprosy and atopic diseases. Int Immunol 11:1801–1810, 1999Google Scholar
  17. 17.
    Murphy KM, Ouyang W, Farrar JD, Yang J, Ranganath S, Asnagli H, Afkarian M, Murphy TL: Signaling and transcription in T helper development. Annu Rev Immunol 18:451–494, 2000Google Scholar
  18. 18.
    Yamada Y, Nakamura A, Hosoda M, Kato T, Asano T, Tonegawa K, Itoh M: Cytokines in pleural liquid for diagnosis of tuberculous pleurisy. Respir Med 95:577–581, 2001Google Scholar
  19. 19.
    Villegas MV, Labrada LA, Saravia NG: Evaluation of polymerase chain reaction, adenosine deaminase and interferon-gamma in pleural fluid for the differential diagnosis of pleural tuberculosis. Chest 118:1355–1364, 2000Google Scholar
  20. 20.
    Gerosa F, Nisii C, Righetti S, Micciolo R, Marchesini M, Cazzadori A, Trinchieri G: CD4(+) T cell clones producing both interferon-gamma and interleukin-10 predominate in bronchoalveolar lavages of active pulmonary tuberculosis patients. Clin Immunol 92:224–234, 1999Google Scholar
  21. 21.
    Condos R, Rom WN, Liu YM, Schluger NW: Local immune responses correlate with presentation and outcome in tuberculosis. Am J Respir Crit Care Med 157:729–735, 1998Google Scholar
  22. 22.
    Taha RA, Kotsimbos TC, Song YL, Menzies D, Hamid Q: IFN-gamma and IL-12 are increased in active compared with inactive tuberculosis. Am J Respir Crit Care Med 155:1135–1139, 1997Google Scholar
  23. 23.
    Somoskovi A, Zissel G, Zipfel PF, Ziegenhagen MW, Klaucke J, Haas H, Schlaak M, Muller-Quernheim J: Different cytokine patterns correlate with the extension of disease in pulmonary tuberculosis. Eur Cytokine Netw 10:135–142, 1999Google Scholar
  24. 24.
    Marchant A, Amedei A, Aszzurri A, Vekemans J, Benagiano M, Tamburini C, Lienhardt C, Corrah T, McAdam KP, Romagnani S, D'Elios MM, DelPrete G: Polarization of PPD-specific T-cell response of patients with tuberculosis from Th0 to Th1 profile after successful antimycobacterial therapy or in vitro conditioning with interferon-alpha or interleukin-12. Am J Respir Cell Mol Biol 24:187–194, 2001Google Scholar
  25. 25.
    Dlugovitzky D, Torres-Morales A, Rateni L, Farroni MA, Largacha C, Molteni O, Bottasso O: Circulating profile of Th1 and Th2 cytokines in tuberculosis patients with different degrees of pulmonary involvement. FEMS Immunol Med Microbiol 18:203–207, 1997Google Scholar
  26. 26.
    Baliko Z, Szereday L, Szekeres-Bartho J: Th2 biased immune response in cases with active Mycobacterium tuberculosis infection and tuberculin anergy. FEMS Immunol Med Microbiol 22:199–204, 1998Google Scholar
  27. 27.
    Seah GT, Scott GM, Rook GAW: Type 2 cytokine gene activation and its relationship to extent of disease in patients with tuberculosis. J Infect Dis 181:385–389, 2000Google Scholar
  28. 28.
    van Crevel R, Karyadi E, Preyers F, Leenders M, Kullberg BJ, Nelwan RH, van der Meer JW: Increased production of interleukin 4 by CD4 and CD8 T cells from patients with tuberculosis is related to the presence of pulmonary cavities. J Infect Dis 181: 1194–1197, 2000Google Scholar
  29. 29.
    Atamas SP, Choi J, Yurovsky VV, White B: An alternative splice variant of human IL-4. IL-4 delta 2 inhibits IL-4-stimulated T-cell proliferation. J Immunol 156:435–441, 1996Google Scholar
  30. 30.
    Jung NGT, Schauer U, Heusser C, Neumann C, Rieger C: Detection of intracellular cytokines by flow cytometry. J Immunol Methods 159:197–207, 1993Google Scholar
  31. 31.
    Mossman TR, Moore KW: The role of IL-10 in cross-regulation of TH1 and TH2 Responses. Immunol Today 12:A49–53, 1991Google Scholar
  32. 32.
    DiPiro JT: Cytokine networks with infection: Mycobacterial infections, leishmaniasis, human immunodeficiency virus infection, and sepsis. Pharmacotherapy 17:205–223, 1997Google Scholar
  33. 33.
    Adams JF, Scholvinck EH, Gie RP, Potter PC, Beyers N, Beyers AD: Decline in total serum IgE after treatment for tuberculosis. Lancet 353:2030–2033, 1999Google Scholar
  34. 34.
    Sieling PA, Modlin RL: Cytokine patterns at the site of mycobacterial infection. Immunobiology 191:378–387, 1994Google Scholar

Copyright information

© Plenum Publishing Corporation 2002

Authors and Affiliations

  • Surendra K. Sharma
    • 1
  • Dipender K. Mitra
    • 2
  • Arumugam Balamurugan
    • 2
  • Ravindra M. Pandey
    • 3
  • Narinder K. Mehra
    • 2
  1. 1.Department of Medicine, AllIndia Institute of Medical Sciences, New Delhi-110 029, India
  2. 2.Department of Transplant Immunology and Immunogenetics, AllIndia Institute of Medical Sciences, New Delhi-110 029, India
  3. 3.Department of Biostatistics, AllIndia Institute of Medical Sciences, New Delhi-110 029, India

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