Genetic Background of the Host and Expression of Natural Resistance and Acquired Immunity to M. tuberculosis

  • Ellen Buschman
  • Emil Skamene
Part of the Infectious Agents and Pathogenesis book series (IAPA)


Recently, the World Health Organization (WHO) outlined a strategic approach for the design of an effective vaccine against tuberculosis.1 A fundamental part of the vaccine development depends on a clearer un derstanding of the role of genetic factors in host responses to Mycobacterium tuberculosis. The aim of this chapter is to review studies that have dealt with the genetic control of susceptibility and resistance to tuberculosis in both humans and animal models.


Human Leukocyte Antigen Migration Inhibition Factor Tuberculosis Patient Recombinant Inbred Purify Protein Derivative 
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  1. 1.
    WHO, 1983, Plan of action for research in the immunology of tuberculosis: Memoran dum from a WHO meeting, 1983, Bull. WHO 61:779–785.Google Scholar
  2. 2.
    Lurie, M. B., and Dannenherg, A. M., Jr., 1965, Macrophage function in infectious disease with inbred rabbits, Bacterial. Rev. 29:466–476.Google Scholar
  3. 3.
    Gray. D. F., 1960, Variations in natural resistance to tuberculosis, J. Hyg. 58:215–227.CrossRefGoogle Scholar
  4. 4.
    Mackaness, G. B., 1968, The immunology of antituberculous immunity, Am. Rev. Respir. Dis. 97:337–344.PubMedGoogle Scholar
  5. 5.
    Lurie, M. B., Zappasodi, P., and Tickner, C., 1955, On the nature of genetic resistance to tuberculosis in the light of the host-parasitic relationships in natively resistant and susceptible rabbits, Am. Rev. Tuberc. Pulm. Dis. 72:297–323.Google Scholar
  6. 6.
    Lurie, M. B., Zappasodi, P., Cardona-Lynch, E., and Dannenberg, A. M., Jr., 1952, The response to the intracutaneous inoculation of BCG as an index of native resistance to tuberculosis, J. Immunol. 68:369–387.PubMedGoogle Scholar
  7. 7.
    Lurie, M. B., Zappasodi, P., Dannenberg, A. M., Jr., and Weiss, G. H., 1952, On the mechanism of genetic resistance to tuberculosis and its mode of inheritance, Am. J. Hum. Genet. 4:302–314.PubMedGoogle Scholar
  8. 8.
    Donovick, R., McKee, C. M., Jambar, W. P., and Rake, G., 1949, Use of the mouse in standardized test for anti-tuberculous activity of compounds of natural or synthetic origin: Choice of mouse strains, Am. Rev. Tuberc. 60:109–120.PubMedGoogle Scholar
  9. 9.
    Sever, J. L., and Youmans, G. P., 1957, The enumeration of non-pathogenic viable tubercule bacilli from the organs of mice, Am. Rev. Tuberc. 75:280–294.PubMedGoogle Scholar
  10. 10.
    Youmans, G. P., and Youmans, A. S., 1972, Response of vaccinated and non-vacci nated syngeneic C57BL/6 mice to infection with M. tuberculosis, Infect. Immun. 6:748– 754.PubMedGoogle Scholar
  11. 11.
    Lynch, C. J., Pierce-Chase, C. H., and Dubos, R., 1965, A genetic study of susceptibility to experimental tuberculosis in mice infected with mammalian tubercle bacilli, J. Exp. Med. 121:1051–1070.PubMedCrossRefGoogle Scholar
  12. 12.
    Gheorghiu, M., Mouton, D., Lecoeur, H., Lagranderie, M., Meuel, J. C., and Biozzi, G., 1985, Resistance of high and low antibody responder lines of mice to the growth of avirulent (BCG) and virulent (H37Rv) strains of mycobacteria, Clin. Exp. Immunol. 59:177–184.PubMedGoogle Scholar
  13. 13.
    Biozzi, G., Mouton, D., Stiffel, C., and Bouthillier, Y., 1984, Major role of macrophage in quantitative genetic regulation of immune responsiveness and anti-infections immunity, Adv. Immunol. 36: 189–234.PubMedCrossRefGoogle Scholar
  14. 14.
    Wiener, E., and Dandieri, A., 1974, Differences in antigen handling by peritoneal macrophages from the Biozzi high and low responder mice, Eur. J. Immunol. 4:457– 463.PubMedCrossRefGoogle Scholar
  15. 15.
    Plant, J., and Glynn, A. A. 1982, Genetic control of resistance to Salmonella typhimurium infection in high and low antibody responder mice, Clin. Exp. Immunol. 50:283–290.PubMedGoogle Scholar
  16. 16.
    Dannenberg, A. M., Jr., 1983, Pathogenesis of tubercu’osis: Native and acquired resistance in animals and humans, in: Immunology of Tuberculosis and Leprosy: A Symposium. U.S.-Japan Cooperative Medical Sciences Program, pp. 344–354.Google Scholar
  17. 17.
    Skamene, E., Gros, P., Forget, A., Kongshavn, P. A. L., St. Charles, C., and Taylor, B. A., 1982, Genetic regulation of resistance to intracellular pathogens, Nature (Lond.) 297:506–510.CrossRefGoogle Scholar
  18. 18.
    Gros, P., Skamene, E., and Forget, A., 1981, Genetic control of natural resistance to Mycobacterium bovis (BCG) in mice, J. Immunol. 127:2417–2421.PubMedGoogle Scholar
  19. 19.
    Potter, M., O’Brien, A. D., Skamene, E., Gros, P., Forget, A., Kongshavn, P. A. L., and Wax, J., 1983, A Balb/c congenic strain of mice that carries a genetic locus (Ityr) controlling resistance to intracellular parasites, Infect. Immun. 40: 1234–1235.PubMedGoogle Scholar
  20. 20.
    Brown, I. N., Glynn, A. A., and Plant, J., 1982, Inbred mouse strain resistance to Mycobacterium lepraemurium follows the Ity/Lsh pattern, Immunology ,47:149–156.PubMedGoogle Scholar
  21. 21.
    Gros, P., Skamene, E., and Forget, A., 1983, Cellular mechanisms of genetically controlled host resistance to Mycobacterium bovis (BCG), J. Immunol. 131:1966–1972.PubMedGoogle Scholar
  22. 22.
    Stach, J-L., Gros, P., Forget, A., and Skamene, E., 1984, Phenotypic expression of genetically-controlled natural resistance to Mycobacterium bovis, J. Immunol. 132: 888– 892.PubMedGoogle Scholar
  23. 23.
    Denis, M., Buschman, E., Forget, A., Pelletier, M., and Skamene, E., 1986, Pleiotropic effects of the Bcg gene: Regulation of la dependent macrophage function, 6th International Congress of Immunology ,abst. No. 5.12.11, 1986.Google Scholar
  24. 24.
    Denis, M., Forget, A., Pelletier, M., Turcotte, R., and Skamene, E., 1986, Control by the Bcg gene of early resistance in mice to infections with BCG substrains and atypical mycobacteria. Clin. Exp. Immunol. 63:517–525.PubMedGoogle Scholar
  25. 25.
    Nickonenko, B. V., Apt, A. S., Moroz, A. M., and Averbakh, M. M., 1985, Genetic analysis of susceptibility of mice to H37Rv tuberculosis infection: Sensitivity versus relative resistance, in: Genetic Control of Host Resistance and Malignancy ,Vol. 3 (E. Skamene, ed.), pp. 291–298, Liss, New York.Google Scholar
  26. 26.
    Blanden, R. V., Lefford, M. J., and Mackaness, G. B., 1969, The host response to Calmette-Guérin bacterius infection in mice, J. Exp. Med. 129:1079–1101.PubMedCrossRefGoogle Scholar
  27. 27.
    Snell, G. D., 1981, Studies in histocompatibility, Science 213:172–178.PubMedCrossRefGoogle Scholar
  28. 28.
    Orme, I. M., and Collins, F. M., 1983, Protection against Mycobacterium tuberculosis infection by adoptive immunotherapy: Requirement for T-cell deficient recipients, J. Exp. Med. 158:74–83.PubMedCrossRefGoogle Scholar
  29. 29.
    Nakamura, R. M., and Tokunaga, T., 1978, Strain difference of delayed-type hyper sensitivity to BCG and its genetic control in mice, Infect. Immun. 22:657–664.PubMedGoogle Scholar
  30. 30.
    Rook, G. A. W., Champion, B. R., Steele, J., Varey, A. M., and Stanford, J. L., 1985, I-A restricted activation by T cell lines of anti-tuberculosis activity in murine macrophages, Clin. Exp. Immunol. 59:414–420.PubMedGoogle Scholar
  31. 31.
    Patterson, R. J., and Youmans, G. P., 1970, Demonstration in tissue culture of lymphocyte-mediated immunity to tuberculosis, Infect. Immun. 1:600–603.PubMedGoogle Scholar
  32. 32.
    Huygen, K., Zhen-Xi, Z., and DeClerc, Q. E., 1983, Failure of athymic nude mice sensitized with bacillus Calmette-Guérin to produce interferon in response to purified protein derivative, Proc. Soc. Exp. Biol. Med. 172:260–264.PubMedGoogle Scholar
  33. 33.
    Nathan, C. F., Murray, H. W., Wiebe, M. E., and Tubin, B. Y., 1983, Identification of interferon-as the lymphokine that activates human macrophage oxidative metabolism and antimicrobial activity, J. Exp. Med. 158:670–689.PubMedCrossRefGoogle Scholar
  34. 34.
    Reggiardo, Z., and Middlebrook, G., 1974, Failure of passive serum transfer of immunity against aerogenic tuberculosis in guinea pigs, Proc. Soc. Exp. Biol. Med. 145:173– 175.PubMedGoogle Scholar
  35. 35.
    Forget, A., Benoit, J. C., Turcotte, R., and Gusew-Chartrand, N., 1976, Enhancement activity of anti-mycobacterial sera in experimental Mycobacterium bovis (BCG) infection in mice, Infect. Immun. 13: 1301–1306.PubMedGoogle Scholar
  36. 36.
    Rosenthal, A. S., and Shevach, E. M., 1974, Function of macrophages in antigen recognition by guinea pig T lymphocytes. I. Requirement for histocompatible macrophages and lymphocytes, J. Exp. Med. 138: 1194–1212.CrossRefGoogle Scholar
  37. 37.
    Neta, R., and Salvin, S. B., 1980, In vivo release oflymphokines in different strains of mice, Cell. Immunol. 51: 173–178.PubMedCrossRefGoogle Scholar
  38. 38.
    Huygen, K., and Palfliet, K., 1984, Strain variation in IFN-production of BCG-sensitized mice challenged with PPD, Cell. Immunol. 85:75–81.PubMedCrossRefGoogle Scholar
  39. 39.
    Hoffenbach, A. ,Lagrange, P. H., and Bach, M. A. ,1985, Strain variation of lymphokine production and specific antibody secretion in mice infected with Mycobacterium lepraemurium, Cell. Immunol. 91: 1–11.PubMedCrossRefGoogle Scholar
  40. 40.
    Pelletier, M., Forget, A., Bourassa, D. ,Gros, P., and Skamene, E., 1982, Immu-nopathology of BCG infection in genetically resistant and susceptible mouse trains, J. Immunol. 129:2179–2185.PubMedGoogle Scholar
  41. 41.
    Buschman, E., Denis, M. ,Forget, A. ,and Skamene, E., 1986, Immunological consequences of innate resistance or susceptibility in congenic mouse strains, in the Sixth International Congress of Immunology ,abst. 5. 12. 10.Google Scholar
  42. 42.
    Bourassa, D., Forget, A., Pelletier, M., Skamene, E., and Turcotte, R., 1985, Cellular immune response to Mycobacterium bovis (BCG) in genetically susceptible and resistant congenic mouse strains, Clin. Exp. Immunol. 62:31–38.PubMedGoogle Scholar
  43. 43.
    Orme, I. M., and Collins, F. M. ,1984, Demonstration of acquired resistance in Bcgrinbred mouse strains infected with a low dose of BCG Montreal, Clin. Exp. Immunol. 56:81–88.PubMedGoogle Scholar
  44. 44.
    Veda, K., Yamazaki, S., and Yanamoto, S., 1983, H-2 I region restriction phenomenon in T cell dependent granuloma formation to Mycobacterium bovis BCG, J. Reticuloen-dothel. Soc. 34:475–484.Google Scholar
  45. 45.
    Closs, O., Lovik, M., Wigzell, H., and Taylor, B. A., 1983, H-2 linked gene(s) influence the granulomatous reaction to viable Mycobacterium lepraemurium in the mouse, Scand. J. Immunol. 18:59–63.PubMedCrossRefGoogle Scholar
  46. 46.
    Yanamoto, K., and Kakinuma, M., 1978, Genetic control of granuloma response to oil-associated BCG cell wall vaccine in mice, Microbiol. Immunol. 22:335–348.Google Scholar
  47. 47.
    Schrier, D. J., Sternick, J. L., Allen, E. M., and Moore, V. L., 1982, Immunogenetics of BCG-induced anergy in mice. Control by genes linked to the IgH complex, J. Immunol. 128:1466–1470.PubMedGoogle Scholar
  48. 48.
    Adu, H. O., Curtis, J. ,and Turk, J. L., 1983, Role of the major histocompatibility complex in resistance and granuloma formation in response to Mycobacterium lep raemurium infection, Infect. Immun. 40:720–725.PubMedGoogle Scholar
  49. 49.
    Ridley, D. S., and Jopling, W. H., 1966, Classification of leprosy according to immunity: A five-group system, Int. J. Leprosy 34:255–273.Google Scholar
  50. 50.
    Myrvang, B., Godal, T., Ridley, D. S., Froland, S. S., and Song, Y. K., 1973, Immune responsiveness to Mycobacterium leprae and other mycobacterial antigens throughout the clinical and histopathological spectrum of leprosy, Clin. Exp. Immunol. 14:541–553.PubMedGoogle Scholar
  51. 51.
    Bullock, W. E., and Fasal, P., 1971, Studies of immune mechanisms in leprosy. III. The role of cellular and humoral factors in impairment of the in vitro immune response, J. Immunol. 106:888–899.PubMedGoogle Scholar
  52. 52.
    Nath, I., van Rood, J. J ,Mehra, N. K., and Vaidya, M. C., 1980, Natural suppressor cells in human leprosy: The role of HLA-D-identical peripheral lymphocytes and macrophages in the in vitro modulation of lymphoproliferative responses, Clin. Exp. Immunol. 42:203–210.PubMedGoogle Scholar
  53. 53.
    Mehra, V., Mason, L. H., Rothman, W., Reinherz, E., Schlossman, S. F., and Bloom, B. R., 1980, Delineation of a human T cell subset responsible for lepromin-induced suppression in leprosy patients, J. Immunol. 125: 1183–1188.PubMedGoogle Scholar
  54. 54.
    Haregwoin, A., Godal, T., Mustafa, A. S., Belehu, A., and Yemaneberhan, T., 1983, T-cell conditioned media reverse T-cell unresponsiveness in lepromatous leprosy, Nature (Lond.) 303:342–344.CrossRefGoogle Scholar
  55. 55.
    Nogueria, N., Kaplan, G., Levy, E., Sarno, E. N., Kusher, P., Piperno, A. G., Vieza, L., Gould, V. C., Levis, W., Steinman, R., Yip, Y., and Cohn, Z. A., 1983, Defective y- interferon production in leprosy: Reversal with antigen and interleukin-2, J. Exp. Med. 158:2165–2170.CrossRefGoogle Scholar
  56. 56.
    Lenzini, L., Rottoli, P., and Rottoli, L., 1977, The spectrum of human tuberculosis, Clin. Exp. Immunol. 27:230–237.PubMedGoogle Scholar
  57. 57.
    Shiratsuchi, H., and Tsuyuguchi, I., 1984, Analysis of T cell subsets by monoclonal antibodies in patients with tuberculosis after in vivo stimulation with purified protein derivative of tuberculin, Clin. Exp. Immunol. 57:271–278.PubMedGoogle Scholar
  58. 58.
    Nash, D. R., and Douglass, J. E., 1980, Anergy in active pulmonary tuberculosis: A comparison between positive and negative reactors and an evaluation of 5 TU and 250 TU skin test doses, Chest 77:32–37.PubMedCrossRefGoogle Scholar
  59. 59.
    Fujiwara, H., Okuda, Y., Fukukawa, T., and Tsuyuguchi, I. ,1982, In vitro tuberculin reactivity of lymphocytes from patients with tuberculous pleurisy, Infect. Immun. 35:402–409.PubMedGoogle Scholar
  60. 60.
    Onwubalili, J. K., Scott, G. M., and Robinson, J. A., 1985, Deficient immune interferon production in tuberculosis, Clin. Exp. Immunol. 59:405–413.PubMedGoogle Scholar
  61. 61.
    Kleinhenz, M. E., Ellner, J. J., and Daniel, T. M., 1981, Immunosuppressive cellular interactions in pulmonary tuberculosis, Clin. Res. 29:448A.Google Scholar
  62. 62.
    Kleinhenz, M. E., and Ellner, J. J., 1985, Immunoregulatory adherent cells in human tuberculosis: Radiation-sensitive antigen-specific suppression by monocytes, J. Infect. Dis. 152:171–176.PubMedCrossRefGoogle Scholar
  63. 63.
    Dausset, J ,1981, The major histocompatibility complex in man: Past, present and future concepts, Science 213: 1469–1474.PubMedCrossRefGoogle Scholar
  64. 64.
    Zinkernagel, R. M., and Doherty, P. C., 1979, MHC-restricted cytotoxic T-cells: Studies on the biological role of polymorphic major transplantation antigens determining T-cell restriction specificity, function and responsiveness, Adv. Immunol. 27:52–177.Google Scholar
  65. 65.
    Erb, P., and Feldmann, M., 1975, The role of macrophages in the generation of T-helper cells. I. The requirement for macrophages in helper cell induction and charac teristics of the macrophage-T-cell interaction, Cell. Immunol. 19:356–367.PubMedCrossRefGoogle Scholar
  66. 66.
    Pawelec, G., Schneider, E. M., Muller, C., and Wernet, P., 1985, HLA-DR, MB-and novel DC-related determinants restrict purified protein derivative of tuberculin (PPD)-stimulated human T cell proliferation, Eur. J. Immunol. 15:12–17.PubMedCrossRefGoogle Scholar
  67. 67.
    Hirschberg, H. ,Bergh, O. J ,and Thorsby, E., 1979, Clonal distribution of HLA restricted antigen-reactive T cells in man, J. Exp. Med. 150: 1271–1276.PubMedCrossRefGoogle Scholar
  68. 68.
    Comstock, G. W., 1978, Tuberculosis in twins: A reanalysis of the Prophit survey, Am. Rev. Respir. Dis. 117:621–624.PubMedGoogle Scholar
  69. 69.
    Fine, P. E. M., 1981, Immunogenetics of susceptibility to leprosy, tuberculosis and leishmaniasis. An epidemiological perspective, Int. J. Leprosy 49:437–454.Google Scholar
  70. 70.
    Singh, S. P. N., Mehra, N. K., Dingley, H. B., Pande, J. N., and Vaidya, M. C., 1983, Human leukocyte antigen (HLA)-linked control of susceptibility to pulmonary tuberculosis and association with HLA-DR types, J. Infect. Dis. 148:676–681.PubMedCrossRefGoogle Scholar
  71. 71.
    Singh, S. P. N., Mehra, N. K., Dingley, H. B., Pande, J. N., and Vaidya, M. C., 1984, HLA haplotype segregation study in multiple case families of pulmonary tuberculosis, Tissue Antigens 23:84–86.PubMedCrossRefGoogle Scholar
  72. 72.
    DeVries, R. R. P., Mehra, N. K., Vaidya, M. C., Gupta, M. D., Meera Khan, P., and van Rood, J. J., 1980, HLA-linked control of susceptibility to tuberculoid leprosy, Tissue Antigens 16:294–304.CrossRefGoogle Scholar
  73. 73.
    Singh, S. P. N., Mehra, N. K., Dingbey, H. B., Pande, J. N., and Vaidya, M. C., 1983, HLA-A, -B, -C., and -DR antigen profile in pulmonary tuberculosis in North India, Tissue Antigens 21:380–384.PubMedCrossRefGoogle Scholar
  74. 74.
    Hwang, C. H., Khan, S., Ende, N., Mangura, B. T., Reichman, L. B., and Chou, J. 1985, The HLA-A, -B, and -DR phenotypes and tuberculosis, Am. Rev. Respir. Dis. 132:382–385.PubMedGoogle Scholar
  75. 75.
    Al-Arif, L. I., Goldstein, R. A., Affronti, L. F., and Janicki, B. W., 1979, HLA-Bwl5 and tuberculosis in a North American black population, Am. Rev. Respir. Dis. 120:1275– 1278.PubMedGoogle Scholar
  76. 76.
    Cox, R. A., Arnold, I. R., Cook, D., and Lundberg, D. I., 1982, HLA phenotypes in Mexican Americans with tuberculosis, Am. Rev. Respir. Dis. 126:653–655.PubMedGoogle Scholar
  77. 77.
    Selby, R., Barnard, J. M., Buchler, S. K., Crumley, J., Larsen, B., and Marshall, W. II., 1978, Tuberculosis associated with HLA-B8 Bfs in a Newfoundland community study, Tissue Antigens 11:403–408.PubMedCrossRefGoogle Scholar
  78. 78.
    Van Eden, W., Holoshitz, J., Nero, Z., Frenkcl, A., Klajman, A., and Cohen, I. R., 1985, Arthritis induced by a T-lymphocyte clone that responds to Mycobacterium tuberculosis and to cartilage proteoglycans, Proc. Natl. Acad. Sci. USA 82:5117–5120.PubMedCrossRefGoogle Scholar

Copyright information

© Plenum Press, New York 1988

Authors and Affiliations

  • Ellen Buschman
    • 1
  • Emil Skamene
    • 1
  1. 1.Department of MedicineMcGill University. Montreal General Hospital Research InstituteMontrealCanada

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