Immunopathology of Tuberculosis

  • Jeffrey K. Actor
  • Robert L. HunterJr.
  • Chinnaswamy Jagannath
Part of the Molecular Pathology Library book series (MPLB, volume 1)


Tuberculosis remains one of the world’s leading infectious causes of death. According to the World Health Organization, the disease is currently spreading at the rate of one person per second. Tuberculosis is a contagious bacterial disease primarily involving the lungs, which develops after inhalation of infected droplets released following a cough from someone infected with the Mycobacterium tuberculosis (M-TB) agent. One third of the world’s population is infected with M-TB, resulting annually in approximately 9 million new tuberculosis cases and approximately 2 million tuberculosis deaths. The virulence of the combination of tuberculosis and human immunodeficiency virus and the rise of multidrug-resistant organisms are ominous developments. In response to the challenge of resurgent disease, numerous investigators are using the best tools of modern science to combat the disease. Nevertheless, there are surprising gaps in our knowledge of tuberculosis, especially secondary tuberculosis, the form that produces most clinical illness and nearly all transmissions of infection.


Mycobacterium Tuberculosis Pulmonary Tuberculosis Delayed Type Hypersensitivity Miliary Tuberculosis Phagosome Maturation 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.


Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.


  1. 1.
    World Health Organization. Global tuberculosis control. Surveillance, planning, financing. In The World Health Report 2006. Geneva: World Health Organization; 2006.Google Scholar
  2. 2.
    Garnier T, Eiglmeier K, Camus JC, et al. The complete genome sequence of Mycobacterium bovis. Proc Natl Acad Sci USA 2003;100(13):7877–7882.CrossRefPubMedGoogle Scholar
  3. 3.
    Camus JC, Pryor MJ, Medigue C, Cole ST. Re-annotation of the genome sequence of Mycobacterium tuberculosis H37Rv. Microbiology 2002;148(Pt 10):2967–2973.PubMedGoogle Scholar
  4. 4.
    Mostrom P, Gordon M, Sola C, et al. Methods used in the molecular epidemiology of tuberculosis. Clin Microbiol Infect 2002;8(11):694–704.CrossRefPubMedGoogle Scholar
  5. 5.
    Gunn FD. Tuberculosis. St Louis: Mosby; 1961.Google Scholar
  6. 6.
    Dannenberg AM Jr. Roles of cytotoxic delayed-type hypersensitivity and macrophage-activating cell-mediated immunity in the pathogenesis of tuberculosis. Immunobiology 1994;191(4–5):461–473.PubMedGoogle Scholar
  7. 7.
    Florey H. Tuberculosis. Philadelphia: WB Saunders; 1958.Google Scholar
  8. 8.
    Garay S. Pulmonary Tuberculosis. Boston: Little Brown & Co.; 1996.Google Scholar
  9. 9.
    Dannenberg AM Jr, Thoashefski JFJ. Pathogenesis of Pulmonary Tuberculosis. New York: McGraw Hill; 1988.Google Scholar
  10. 10.
    Dannenberg AM Jr, Collins FM. Progressive pulmonary tuberculosis is not due to increasing numbers of viable bacilli in rabbits, mice and guinea pigs, but is due to a continuous host response to mycobacterial products. Tuberculosis (Edinb) 2001;81(3):229–242.CrossRefGoogle Scholar
  11. 11.
    Kumar V, Fausto N, Abbas A. Pathologic Basis of Disease, 7th ed. Philadelphia: WB Saunders; 2005.Google Scholar
  12. 12.
    Alcais A, Fieschi C, Abel L, Casanova JL. Tuberculosis in children and adults: two distinct genetic diseases. J Exp Med 2005;202(12):1617–1621.CrossRefPubMedGoogle Scholar
  13. 13.
    Osler W. Tuberculosis. New York: D. Appleton and Co.; 1892.Google Scholar
  14. 14.
    Slavin RE. Late generalized tuberculosis: a clinical and pathologic analysis of a diagnostic puzzle and a changing pattern. Pathol Annu 1981;16(Pt 1):81–99.PubMedGoogle Scholar
  15. 15.
    Slavin RE, Walsh TJ, Pollack AD. Late generalized tuberculosis: a clinical pathologic analysis and comparison of 100 cases in the preantibiotic and antibiotic eras. Medicine (Baltimore) 1980;59(5):352–366.Google Scholar
  16. 16.
    North RJ, Jung YJ. Immunity to tuberculosis. Annu Rev Immunol 2004;22:599–623.CrossRefPubMedGoogle Scholar
  17. 17.
    Smith I. Mycobacterium tuberculosis pathogenesis and molecular determinants of virulence. Clin Microbiol Rev 2003;16(3):463–496.CrossRefPubMedGoogle Scholar
  18. 18.
    Levine ER. Classification of reinfection pulmonary tuberculosis. In E. Hayes E, ed. The Fundamentals of Pulmonary Tuberculosis and its Complications. Springfield, IL: Charles C. Thomas; 1949:97–113.Google Scholar
  19. 19.
    Ulrichs T, Kaufmann SH. New insights into the function of granulomas in human tuberculosis. J Pathol 2006;208(2):261–269.CrossRefPubMedGoogle Scholar
  20. 20.
    Hunter RL, Olsen M, Jagannath C, Actor JK. Trehalose 6,6′-dimycolate and lipid in the pathogenesis of caseating granulomas of tuberculosis in mice. Am J Pathol 2006;168(4):1249–1261.CrossRefPubMedGoogle Scholar
  21. 21.
    Aaron L, Saadoun D, Calatroni I, et al. Tuberculosis in HIV-infected patients: a comprehensive review. Clin Microbiol Infect 2004;10(5):388–398.CrossRefPubMedGoogle Scholar
  22. 22.
    Ledru E, Ledru S, Zoubga A. Granuloma formation and tuberculosis transmission in HIV-infected patients. Immunol Today 1999;20(7):336–337.CrossRefPubMedGoogle Scholar
  23. 23.
    McMurray DN, Collins FM, Dannenberg AM Jr, Smith DW. Pathogenesis of experimental tuberculosis in animal models. Curr Top Microbiol Immunol 1996;215:157–179.PubMedGoogle Scholar
  24. 24.
    Druilhe P, Hagan P, Rook GA. The importance of models of infection in the study of disease resistance. Trends Microbiol 2002;10(10 Suppl):S38–S46.CrossRefPubMedGoogle Scholar
  25. 25.
    Kaufmann SH, Cole ST, Mizrahi V, et al. Mycobacterium tuberculosis and the host response. J Exp Med 2005;201(11):1693–1697.CrossRefPubMedGoogle Scholar
  26. 26.
    Kaufmann SH. Protection against tuberculosis: cytokines, T cells, and macrophages. Ann Rheum Dis 2002;61(Suppl 2):ii54–ii58.PubMedGoogle Scholar
  27. 27.
    Rook GA, Zumla A. Advances in the immunopathogenesis of pulmonary tuberculosis. Curr Opin Pulm Med 2001;7(3):116–123.CrossRefPubMedGoogle Scholar
  28. 28.
    Maes HH, Causse JE, Maes RF. Tuberculosis I: a conceptual frame for the immunopathology of the disease. Med Hypotheses 1999;52(6):583–593.CrossRefPubMedGoogle Scholar
  29. 29.
    Actor JK, Leonard CD, Watson VE, Wells A, et al. Cytokine mRNA expression and serum cortisol evaluation during murine lung inflammation induced by Mycobacterium tuberculosis. Comb Chem High Throughput Screen 2000;3(4):343–51.PubMedGoogle Scholar
  30. 30.
    Johnson CM, Cooper AM, Frank AA, Orme IM. Adequate expression of protective immunity in the absence of granuloma formation in Mycobacterium tuberculosis-infected mice with a disruption in the intracellular adhesion molecule 1 gene. Infect Immun 1998;66(4):1666–1670.PubMedGoogle Scholar
  31. 31.
    Orme IM, Andersen P, Boom WH. T cell response to Mycobacterium tuberculosis. J Infect Dis 1993;167(6):1481–1497.PubMedGoogle Scholar
  32. 32.
    Orme IM, Lee BY, Appelberg R, et al. T cell response in acquired protective immunity to Mycobacterium tuberculosis infection. Bull Int Union Tuberc Lung Dis 1991;66(1):7–13.PubMedGoogle Scholar
  33. 33.
    Actor JK, Olsen M, Jagannath C, Hunter RL. Relationship of survival, organism containment, and granuloma formation in acute murine tuberculosis. J Interferon Cytokine Res 1999;19(10):1183–1193.CrossRefPubMedGoogle Scholar
  34. 34.
    Flynn JL, Chan J. What’s good for the host is good for the bug. Trends Microbiol 2005;13(3):98–102.CrossRefPubMedGoogle Scholar
  35. 35.
    Karakousis PC, Bishai WR, Dorman SE. Mycobacterium tuberculosis cell envelope lipids and the host immune response. Cell Microbiol 2004;6(2):105–116.CrossRefPubMedGoogle Scholar
  36. 36.
    Fenton MJ, Vermeulen MW. Immunopathology of tuberculosis: roles of macrophages and monocytes. Infect Immun 1996;64(3):683–690.PubMedGoogle Scholar
  37. 37.
    Perez RL, Roman J, Roser S, et al. Cytokine message and protein expression during lung granuloma formation and resolution induced by the mycobacterial cord factor trehalose-6,6′-dimycolate. J Interferon Cytokine Res 2000;20(9):795–804.CrossRefPubMedGoogle Scholar
  38. 38.
    Hickman SP, Chan J, Salgame P. Mycobacterium tuberculosis induces differential cytokine production from dendritic cells and macrophages with divergent effects on naive T cell polarization. J Immunol 2002;168(9):4636–4642.PubMedGoogle Scholar
  39. 39.
    Brightbill HD, Libraty DH, Krutzik SR, et al. Host defense mechanisms triggered by microbial lipoproteins through toll-like receptors. Science 1999;285(5428):732–736.CrossRefPubMedGoogle Scholar
  40. 40.
    Scanga CA, Bafica A, Feng CG, et al. MyD88-deficient mice display a profound loss in resistance to Mycobacterium tuberculosis associated with partially impaired Th1 cytokine and nitric oxide synthase 2 expression. Infect Immun 2004;72(4):2400–2404.CrossRefPubMedGoogle Scholar
  41. 41.
    Feng CG, Scanga CA, Collazo-Custodio CM, et al. Mice lacking myeloid differentiation factor 88 display profound defects in host resistance and immune responses to Mycobacterium avium infection not exhibited by Toll-like receptor 2 (TLR2)-and TLR4-deficient animals. J Immunol 2003;171(9):4758–4764.PubMedGoogle Scholar
  42. 42.
    Shi S, Blumenthal A, Hickey CM, et al. Expression of many immunologically important genes in Mycobacterium tuberculosis-infected macrophages is independent of both TLR2 and TLR4 but dependent on IFN-alphabeta receptor and STAT1. J Immunol 2005;175(5):3318–3328.PubMedGoogle Scholar
  43. 43.
    Bulut Y, Michelsen KS, Hayrapetian L, et al. Mycobacterium tuberculosis heat shock proteins use diverse Toll-like receptor pathways to activate pro-inflammatory signals. J Biol Chem 2005;280(22):20961–20967.CrossRefPubMedGoogle Scholar
  44. 44.
    Quesniaux V, Fremond C, Jacobs M, et al. Toll-like receptor pathways in the immune responses to mycobacteria. Microbes Infect 2004;6(10):946–959.CrossRefPubMedGoogle Scholar
  45. 45.
    Bafica A, Scanga CA, Feng CG, et al. TLR9 regulates Th1 responses and cooperates with TLR2 in mediating optimal resistance to Mycobacterium tuberculosis. J Exp Med 2005;202(12):1715–1724.CrossRefPubMedGoogle Scholar
  46. 46.
    Trinchieri G, Gerosa F. Immunoregulation by interleukin-12. J Leuk Biol 1996;59(4):505–511.Google Scholar
  47. 47.
    Cooper AM, Flynn JL. The protective immune response to Mycobacterium tuberculosis. Curr Opin Immunol 1995;7(4):512–516.CrossRefPubMedGoogle Scholar
  48. 48.
    Cooper AM, Magram J, Ferrante J, Orme IM. Interleukin 12 (IL-12) is crucial to the development of protective immunity in mice intravenously infected with Mycobacterium tuberculosis. J Exp Med 1997;186(1):39–45.CrossRefPubMedGoogle Scholar
  49. 49.
    Cooper AM, Roberts AD, Rhoades ER, et al. The role of interleukin-12 in acquired immunity to Mycobacterium tuberculosis infection. Immunology 1995;84(3):423–432.PubMedGoogle Scholar
  50. 50.
    Orme IM, Cooper AM. Cytokine/chemokine cascades in immunity to tuberculosis. Immunol Today 1999;20(7):307–312.CrossRefPubMedGoogle Scholar
  51. 51.
    Saunders BM, Cooper AM. Restraining mycobacteria: role of granulomas in mycobacterial infections. Immunol Cell Biol 2000;78(4):334–341.CrossRefPubMedGoogle Scholar
  52. 52.
    Mohan VP, Scanga CA, Yu K, et al. Effects of tumor necrosis factor alpha on host immune response in chronic persistent tuberculosis: possible role for limiting pathology. Infect Immun 2001;69(3):1847–1855.CrossRefPubMedGoogle Scholar
  53. 53.
    Serbina NV, Liu CC, Scanga CA, Flynn JL. CD8+ CTL from lungs of Mycobacterium tuberculosis-infected mice express perforin in vivo and lyse infected macrophages. J Immunol 2000;165(1):353–363.PubMedGoogle Scholar
  54. 54.
    Scanga CA, Mohan VP, Joseph H, et al. Reactivation of latent tuberculosis: variations on the Cornell murine model. Infect Immun 1999;67(9):4531–4538.PubMedGoogle Scholar
  55. 55.
    Indrigo J, Hunter RL Jr, Actor JK. Influence of trehalose 6,6′-dimycolate (TDM) during mycobacterial infection of bone marrow macrophages. Microbiology 2002;148(Pt 7):1991–1998.PubMedGoogle Scholar
  56. 56.
    Russell DG. Phagosomes, fatty acids and tuberculosis. Nat Cell Biol 2003;5(9):776–778.CrossRefPubMedGoogle Scholar
  57. 57.
    Pieters J, Gatfield J. Hijacking the host: survival of pathogenic mycobacteria inside macrophages. Trends Microbiol 2002;10(3):142–146.CrossRefPubMedGoogle Scholar
  58. 58.
    Vergne I, Chua J, Lee HH, et al. Mechanism of phagolysosome biogenesis block by viable Mycobacterium tuberculosis. Proc Natl Acad Sci USA 2005;102(11):4033–4038.CrossRefPubMedGoogle Scholar
  59. 59.
    Deretic V, Singh S, Master S, et al. Mycobacterium tuberculosis inhibition of phagolysosome biogenesis and autophagy as a host defense mechanism. Cell Microbiol 2006;8(5):719–727.CrossRefPubMedGoogle Scholar
  60. 60.
    Ernst JD. Macrophage receptors for Mycobacterium tuberculosis. Infect Immun 1998;66(4):1277–1281.PubMedGoogle Scholar
  61. 61.
    VanHeyningen TK, Collins HL, Russell DG. IL-6 produced by macrophages infected with Mycobacterium species suppresses T cell responses. J Immunol 1997;158(1):330–337.PubMedGoogle Scholar
  62. 62.
    Stenger S, Niazi KR, Modlin RL. Down-regulation of CD1 on antigen-presenting cells by infection with Mycobacterium tuberculosis. J Immunol 1998;161(7):3582–3588.PubMedGoogle Scholar
  63. 63.
    Ramachandra L, Smialek JL, Shank SS, et al. Phagosomal processing of Mycobacterium tuberculosis antigen 85B is modulated independently of mycobacterial viability and phagosome maturation. Infect Immun 2005;73(2):1097–1105.CrossRefPubMedGoogle Scholar
  64. 64.
    Ramachandra L, Noss E, Boom WH, Harding CV. Processing of Mycobacterium tuberculosis antigen 85B involves intraphagosomal formation of peptide-major histocompatibility complex II complexes and is inhibited by live bacilli that decrease phagosome maturation. J Exp Med 2001;194(10):1421–1432.CrossRefPubMedGoogle Scholar
  65. 65.
    Actor JK, Indrigo J, Beachdel CM, et al. A. Mycobacterial glycolipid cord factor trehalose 6,6’-dimycolate causes a decrease in serum cortisol during the granulomatous response. Neuroimmunomodulation 2002;10(5):270–282.CrossRefPubMedGoogle Scholar
  66. 66.
    Rook GA, Hernandez-Pando R. The pathogenesis of tuberculosis. Annu Rev Microbiol 1996;50:259–284.CrossRefPubMedGoogle Scholar
  67. 67.
    Dheda K, Booth H, Huggett JF, et al. Lung remodeling in pulmonary tuberculosis. J Infect Dis 2005;192(7):1201–1209.CrossRefPubMedGoogle Scholar
  68. 68.
    Feng CG, Bean AG, Hooi H, et al. Increase in gamma interferon-secreting CD8(+), as well as CD4(+), T cells in lungs following aerosol infection with Mycobacterium tuberculosis. Infect Immun 1999;67(7):3242–3247.PubMedGoogle Scholar
  69. 69.
    Peters W, Ernst JD. Mechanisms of cell recruitment in the immune response to Mycobacterium tuberculosis. Microbes Infect 2003;5(2):151–158.CrossRefPubMedGoogle Scholar
  70. 70.
    Actor JK, Breij E, Wetsel RA, et al. A role for complement C5 in organism containment and granulomatous response during murine tuberculosis. Scand J Immunol 2001;53(5):464–474.CrossRefPubMedGoogle Scholar
  71. 71.
    Armstrong JA, Hart PD. Phagosome-lysosome interactions in cultured macrophages infected with virulent tubercle bacilli. Reversal of the usual nonfusion pattern and observations on bacterial survival. J Exp Med 1975;142(1):1–16.CrossRefPubMedGoogle Scholar
  72. 72.
    Via LE, Deretic D, Ulmer RJ, et al. Arrest of mycobacterial phagosome maturation is caused by a block in vesicle fusion between stages controlled by rab5 and rab7. J Biol Chem 1997;272(20):13326–13331.CrossRefPubMedGoogle Scholar
  73. 73.
    Sturgill-Koszycki S, Schlesinger PH, Chakraborty P, et al. Lack of acidification in Mycobacterium phagosomes produced by exclusion of the vesicular proton-ATPase. Science 1994;263(5147):678–681.CrossRefPubMedGoogle Scholar
  74. 74.
    Kusner DJ, Barton JA. ATP stimulates human macrophages to kill intracellular virulent Mycobacterium tuberculosis via calcium-dependent phagosome-lysosome fusion. J Immunol 2001;167(6):3308–3315.PubMedGoogle Scholar
  75. 75.
    Clemens DL, Lee BY, Horwitz MA. The Mycobacterium tuberculosis phagosome in human macrophages is isolated from the host cell cytoplasm. Infect Immun 2002;70(10):5800–5807.CrossRefPubMedGoogle Scholar
  76. 76.
    Indrigo J, Hunter RL Jr, Actor JK. Cord factor trehalose 6,6′-dimycolate (TDM) mediates trafficking events during mycobacterial infection of murine macrophages. Microbiology 2003;149(Pt 8):2049–2059.CrossRefPubMedGoogle Scholar
  77. 77.
    Clemens DL, Horwitz MA. The Mycobacterium tuberculosis phagosome interacts with early endosomes and is accessible to exogenously administered transferrin. J Exp Med 1996;184(4):1349–1355.CrossRefPubMedGoogle Scholar
  78. 78.
    Sturgill-Koszycki S, Schaible UE, Russell DG. Mycobacterium-containing phagosomes are accessible to early endosomes and reflect a transitional state in normal phagosome biogenesis. EMBO J 1996;15(24):6960–6968.PubMedGoogle Scholar
  79. 79.
    Ullrich HJ, Beatty WL, Russell DG. Direct delivery of procathepsin D to phagosomes: implications for phagosome biogenesis and parasitism by Mycobacterium. Eur J Cell Biol 1999;78(10):739–748.PubMedGoogle Scholar
  80. 80.
    Vergne I, Fratti RA, Hill PJ, et al. Mycobacterium tuberculosis phagosome maturation arrest: mycobacterial phosphatidylinositol analog phosphatidylinositol mannoside stimulates early endosomal fusion. Mol Biol Cell 2004;15(2):751–760.CrossRefPubMedGoogle Scholar
  81. 81.
    Fratti RA, Chua J, Vergne I, Deretic V. Mycobacterium tuberculosis glycosylated phosphatidylinositol causes phagosome maturation arrest. Proc Natl Acad Sci USA 2003;100(9):5437–5442.CrossRefPubMedGoogle Scholar
  82. 82.
    Nathan C, Shiloh MU. Reactive oxygen and nitrogen intermediates in the relationship between mammalian hosts and microbial pathogens. Proc Natl Acad Sci USA 2000;97(16):8841–8848.CrossRefPubMedGoogle Scholar
  83. 83.
    Jagannath C, Actor JK, Hunter RL Jr. Induction of nitric oxide in human monocytes and monocyte cell lines by Mycobacterium tuberculosis. Nitric Oxide 1998;2(3):174–186.CrossRefPubMedGoogle Scholar
  84. 84.
    Ng VH, Cox JS, Sousa AO, et al. Role of KatG catalaseperoxidase in mycobacterial pathogenesis: countering the phagocyte oxidative burst. Mol Microbiol 2004;52(5):1291–1302.CrossRefPubMedGoogle Scholar
  85. 85.
    Miller BH, Fratti RA, Poschet JF, et al. Mycobacteria inhibit nitric oxide synthase recruitment to phagosomes during macrophage infection. Infect Immun 2004;72(5):2872–2878.CrossRefPubMedGoogle Scholar
  86. 86.
    Scanga CA, Mohan VP, Yu K, et al. Depletion of CD4(+) T cells causes reactivation of murine persistent tuberculosis despite continued expression of interferon gamma and nitric oxide synthase 2. J Exp Med 2000;192(3):347–358.CrossRefPubMedGoogle Scholar
  87. 87.
    Chan J, Flynn J. The immunological aspects of latency in tuberculosis. Clin Immunol 2004;110(1):2–12.CrossRefPubMedGoogle Scholar
  88. 88.
    Jagannath C, Hoffmann H, Sepulveda E, et al. Hypersusceptibility of A/J mice to tuberculosis is in part due to a deficiency of the fifth complement component (C5). Scand J Immunol 2000;52(4):369–379.CrossRefPubMedGoogle Scholar
  89. 89.
    Rook GA, al Attiyah R. Cytokines and the Koch phenomenon. Tubercle 1991;72(1):13–20.CrossRefPubMedGoogle Scholar
  90. 90.
    Rook GA, Stanford JL. The Koch phenomenon and the immunopathology of tuberculosis. Curr Top Microbiol Immunol 1996;215:239–262.PubMedGoogle Scholar
  91. 91.
    Rook GA, al Attiyah R, Filley E. New insights into the immunopathology of tuberculosis. Pathobiology 1991;59(3):148–52.CrossRefPubMedGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC. 2008

Authors and Affiliations

  • Jeffrey K. Actor
    • 1
  • Robert L. HunterJr.
    • 1
  • Chinnaswamy Jagannath
    • 1
  1. 1.Department of Pathology and Laboratory MedicineUniversity of Texas-Houston Medical SchoolHoustonUSA

Personalised recommendations