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Chapter 3 : Pathophysiology and Immunology

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Abstract:

This chapter talks about pathophysiology and immunology of tuberculosis. The pathogenesis of human pulmonary tuberculosis can be considered as a series of battles between the host and the tubercle bacillus. The chapter discusses the measures for reducing the incidence of new cases of clinical tuberculosis, and gives an overview of five stages of pulmonary tuberculosis. It reviews the innate and acquired (adaptive) immune factors that play a role in tuberculosis. The term tissue-damaging delayed-type hypersensitivity (DTH) is used for the immunological reaction that causes necrosis. The chapter explores the major types of lymphocytes. Additional insight has recently been gained into the adjuvanticity of tuberculosis vaccines. In dermal BCG lesions, the percentage of mononuclear cells containing cytokine mRNA and protein was highest during the first 3 days. This finding suggests that the most effective tuberculosis vaccines would contain not only the most appropriate mycobacterial antigens but also mycobacterial adjuvants that recruit the largest number of macrophages, lymphocytes, and dendritic cells (DCs) into local sites of antigen deposition. Combination vaccines which consist of BCG and one or more booster immunizations with important mycobacterial antigens (including those produced by DNA vaccines) will probably provide the most effective protection against active disease. The major research advances in immunology that have direct bearing on the pathogenesis of tuberculosis are also described in the chapter. They include interactions between innate immunity and acquired immunity, interactions among the cytokines, and upregulating and downregulating mechanisms of both inflammatory and immune response.

Citation: Dannenberg, Jr. A, Converse P. 2011. Pathophysiology and Immunology, p 29-65. In Schlossberg D (ed), Tuberculosis and Nontuberculous Mycobacterial Infections, Sixth Edition. ASM Press, Washington, DC. doi: 10.1128/9781555817138.ch3

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Image of Figure 1.
Figure 1.

Stages in pulmonary tuberculosis. (A) Stage 1: an AM that has ingested and is destroying the two tubercle bacilli in the phagocytic vacuole. The cytoplasm of this macrophage is darkly shaded to depict the high degree of AM activation, i.e., high levels of lysosomal and oxidative enzymes ( ). (B) Stage 2: an early primary tubercle, in which tubercle bacilli have multiplied logarithmically within macrophages that have emigrated from the bloodstream into the developing lesion. These newly arriving phagocytes are nonactivated, so the cytoplasm of these macrophages is unshaded to depict the lack of activation. In fact, virulent tubercle bacilli grow well within the phagocytic vacuoles of these nonactivated macrophages. Stage 2 is called the stage of symbiosis ( ) since the bacilli are multiplying, the macrophages are accumulating, and neither is destroyed. (C) Stage 3: a tubercle 3 weeks of age with a caseous necrotic center and a peripheral accumulation of partly activated macrophages (lightly shaded) and lymphocytes (small dark cells). The first stages of caseation occur when the tissue-damaging DTH response (to the tuberculin-like products of the bacilli) kills the nonactivated macrophages that have allowed the bacilli to grow logarithmically within them. The dead and dying macrophages are depicted as fragmented cell membranes. Intact and fragmented bacilli are present, both within macrophages and within the caseum. Reprinted with permission from ( ) (see also pages 23 to 29 in reference ).

Citation: Dannenberg, Jr. A, Converse P. 2011. Pathophysiology and Immunology, p 29-65. In Schlossberg D (ed), Tuberculosis and Nontuberculous Mycobacterial Infections, Sixth Edition. ASM Press, Washington, DC. doi: 10.1128/9781555817138.ch3
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Image of Figure 2.
Figure 2.

Changes in the number of virulent human-type tubercle bacilli in the lungs of natively resistant rabbits and natively susceptible rabbits at different intervals after the quantitative airborne inhalation of these bacilli ( ). By 7 days after infection, the resistant animals had inhibited the growth of the bacilli 20 to 30 times more effectively than did the susceptible animals, but from then on, the two curves were parallel. At 4 to 5 weeks, susceptible animals had about 13 times the number of primary pulmonary tubercles present in the resistant animals. Means and standard errors are shown. The number of bacilli in the lungs of the resistant group failed to decrease during the period illustrated, because liquefaction with extracellular multiplication of the bacilli readily occurred in the resistant rabbits but only rarely occurred in the susceptible rabbits ( ). The macrophages of the resistant rabbits apparently developed higher levels of hydrolytic enzymes ( ). Reprinted with permission from ( ) (see also page 23 in reference ).

Citation: Dannenberg, Jr. A, Converse P. 2011. Pathophysiology and Immunology, p 29-65. In Schlossberg D (ed), Tuberculosis and Nontuberculous Mycobacterial Infections, Sixth Edition. ASM Press, Washington, DC. doi: 10.1128/9781555817138.ch3
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Image of Figure 3.
Figure 3.

(A) Stage 4a: an established tubercle 4 to 5 weeks of age representing that found in Lurie’s susceptible rabbits. It has an enlarging caseous center. The bacilli escaping from the edge of this center are ingested by nonactivated (incompetent) macrophages. In such macrophages, the bacilli again find a favorable intracellular environment in which to multiply. They do so until again the tissue-damaging immune response kills these new bacillus-laden macrophages and the area of caseous necrosis enlarges. This sequence may be repeated many times. The living tissue is destroyed, and the bacilli spread by the lymphatic and hematogenous routes to other sites, where the tissue destruction continues. Several partly activated macrophages (lightly shaded) are included to show that these susceptible rabbits develop only weak CMI. This pattern of tuberculosis is seen in immunosuppressed individuals, including nonterminal HIV/AIDS patients. (B) Stage 4b: an established tubercle 4 or 5 weeks of age representing those found in Lurie’s resistant rabbits. The caseous center remains small because the bacilli escaping from its edge are ingested by highly activated (competent) macrophages (darkly shaded) that surround the caseum. In such activated macrophages, the bacilli cannot multiply and are eventually destroyed. Such effective macrophages are the result of activation by T cells and their cytokines. If the caseous center remains solid and does not liquefy, the disease will be arrested by this CMI process, because further tissue destruction does not occur. This scenario occurs in healthy immunocompetent human beings who show positive tuberculin reactions and yet no clinical and often no X-ray evidence of the disease. Reprinted with permission from ( ) (see also page 27 in reference ).

Citation: Dannenberg, Jr. A, Converse P. 2011. Pathophysiology and Immunology, p 29-65. In Schlossberg D (ed), Tuberculosis and Nontuberculous Mycobacterial Infections, Sixth Edition. ASM Press, Washington, DC. doi: 10.1128/9781555817138.ch3
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Image of Figure 4.
Figure 4.

Stage 5: a recently formed small cavity discharging liquefied caseous material into a bronchus. In this liquefied material, the bacilli have multiplied profusely and extracellularly. With such large numbers of bacilli, there is an increased likelihood of a mutation resulting in antimicrobial resistance. Also, the large quantities of bacilli and their antigens in the liquefied caseum are too much for even a formerly effective CMI to control, and the DTH reaction to them destroys nearby tissues, including the wall of an adjacent bronchus (illustrated here). The bacilli are then discharged into the airways, where they disseminate to other parts of the lung and to the environment. Reprinted with permission from ( ) (see also page 29 in reference ).

Citation: Dannenberg, Jr. A, Converse P. 2011. Pathophysiology and Immunology, p 29-65. In Schlossberg D (ed), Tuberculosis and Nontuberculous Mycobacterial Infections, Sixth Edition. ASM Press, Washington, DC. doi: 10.1128/9781555817138.ch3
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Image of Figure 5.
Figure 5.

A tissue section of a 10-day (rabbit) pulmonary BCG lesion. In the caseous center are disintegrated β-galactosidase-negative epithelioid cells and more than 10 faintly stained tubercle bacilli. (β-Galactosidase activity is our histochemical marker for activated macrophages that are capable of destroying tubercle bacilli [ ].) Around the caseous center are viable, poorly activated β-galactosidase-negative mononuclear cells (DCs, macrophages, and lymphocytes) from the bloodstream, which control the fate of the lesion. The highly activated pulmonary AM, staining 3+ and 4+ for β-galactosidase, have accumulated in the surrounding alveolar spaces, rather far from the bacilli in the center. Although this lesion was produced by the intravenous injection of tubercle bacilli, tubercles produced by the inhalation of bacilli should show the same pattern. Specifically, bacilli are released from weakly activated pulmonary AM that failed to control the initial bacillary multiplication. These bacilli and host cytokines chemotactically attract new nonactivated macrophages (from the bloodstream), which cannot control the multiplication of tubercle bacilli in their cytoplasm (until they become activated by antigen-specific T lymphocytes). This photograph clearly demonstrates that pulmonary AM play a minor role in controlling the fate of established pulmonary tubercles, but these AM play a major role in destroying endogenous and exogenous tubercle bacilli that enter the alveolar spaces. Magnification, ×400. Reprinted with permission from ( ) (see also page 25 in reference ).

Citation: Dannenberg, Jr. A, Converse P. 2011. Pathophysiology and Immunology, p 29-65. In Schlossberg D (ed), Tuberculosis and Nontuberculous Mycobacterial Infections, Sixth Edition. ASM Press, Washington, DC. doi: 10.1128/9781555817138.ch3
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Image of Figure 6.
Figure 6.

Tissue section of a tuberculous lesion from one of Lurie’s genetically susceptible rabbits 2 weeks after the inhalation of virulent human-type tubercle bacilli. The nonactivated macrophages from the bloodstream contain numerous (rod-shaped) acid-fast bacilli. Two weeks is near the end of stage 2, the stage of symbiosis: the bacilli have grown logarithmically within these nonactivated macrophages with no apparent damage to the cells. Magnification, ×855. Reprinted with permission from ( ) (see also page 25 in reference ).

Citation: Dannenberg, Jr. A, Converse P. 2011. Pathophysiology and Immunology, p 29-65. In Schlossberg D (ed), Tuberculosis and Nontuberculous Mycobacterial Infections, Sixth Edition. ASM Press, Washington, DC. doi: 10.1128/9781555817138.ch3
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Image of Figure 7.
Figure 7.

Tissue section of a 12-day (rabbit) dermal BCG lesion. Highly activated macrophages (stained dark blue for β-galactosidase) surround the caseous center. Therefore, bacilli released from dead and dying macrophages will now be ingested by macrophages able to inhibit intracellular bacillary growth. Magnification, ×120. Reprinted with permission from ( ) (see also page 101 in reference ).

Citation: Dannenberg, Jr. A, Converse P. 2011. Pathophysiology and Immunology, p 29-65. In Schlossberg D (ed), Tuberculosis and Nontuberculous Mycobacterial Infections, Sixth Edition. ASM Press, Washington, DC. doi: 10.1128/9781555817138.ch3
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Image of Figure 8.
Figure 8.

Tubercle bacilli growing profusely in the liquefied caseum in the wall of an early rabbit pulmonary cavity. Such bacillary growth occurs when the metabolism of the bacilli changes from dormancy in solid caseum to extracellular growth in liquefied caseum. For bacillary growth to occur, the composition of the liquefied caseum must be favorable. Also, oxygen (from the airways) enhances such growth ( ). Similar bacillary growth has been found in many human tuberculosis cavities. Magnification, ×600. Reprinted with permission from ( ) (see also page 45 in reference ).

Citation: Dannenberg, Jr. A, Converse P. 2011. Pathophysiology and Immunology, p 29-65. In Schlossberg D (ed), Tuberculosis and Nontuberculous Mycobacterial Infections, Sixth Edition. ASM Press, Washington, DC. doi: 10.1128/9781555817138.ch3
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Image of Figure 9.
Figure 9.

Tissue section of an area of tuberculous pneumonia in a lung of a 47-year-old man. A large proportion of the cellular exudate in the alveolar spaces has undergone caseous necrosis, and infiltrating cells thicken the alveolar septa. Magnification, ×266. From the collection of the late A. R. Rich and W. G. MacCallum, Department of Pathology, School of Medicine, The Johns Hopkins University (see also page 41 in reference ).

Citation: Dannenberg, Jr. A, Converse P. 2011. Pathophysiology and Immunology, p 29-65. In Schlossberg D (ed), Tuberculosis and Nontuberculous Mycobacterial Infections, Sixth Edition. ASM Press, Washington, DC. doi: 10.1128/9781555817138.ch3
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Image of Figure 10.
Figure 10.

An example of liquefaction and ulceration in the skin of a rabbit produced by the intradermal injection of BCG. In the photograph on the right, the lesion contents were exposed by cutting it with a scalpel. Reprinted with permission from (Edinburgh) ( ).

Citation: Dannenberg, Jr. A, Converse P. 2011. Pathophysiology and Immunology, p 29-65. In Schlossberg D (ed), Tuberculosis and Nontuberculous Mycobacterial Infections, Sixth Edition. ASM Press, Washington, DC. doi: 10.1128/9781555817138.ch3
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Image of Figure 11.
Figure 11.

CMI activating macrophages in a tuberculous lesion. Mononuclear phagocytes that entered the lesion from the bloodstream are activated by the cytokines of antigen-specific T lymphocytes that had also entered the lesion. (“LK” stands for lymphokines, the former name for lymphocyte cytokines.) Antigen-specific lymphocytes produce these cytokines when stimulated by the bacillus and its products. Only activated macrophages seem capable of destroying the tubercle bacillus. Reprinted with permission from ( ) (see also page 100 in reference ).

Citation: Dannenberg, Jr. A, Converse P. 2011. Pathophysiology and Immunology, p 29-65. In Schlossberg D (ed), Tuberculosis and Nontuberculous Mycobacterial Infections, Sixth Edition. ASM Press, Washington, DC. doi: 10.1128/9781555817138.ch3
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Image of Figure 12.
Figure 12.

Tissue section of a 21-day rabbit dermal BCG lesion, showing a group of activated macrophages (epithelioid cells) stained darkly for the lysosomal enzyme β-galactosidase. (As stated in the legend to Fig. 5 , β-galactosidase activity is our histochemical marker for activated macrophages that are capable of destroying tubercle bacilli [ ].) Although perifocal tuberculous granulation tissue contains hundreds of macrophages, only those macrophages in locations where tubercle bacilli (and their products) are present become activated and develop the power to destroy the bacillus. In other words, the acquired cellular resistance (produced by CMI) is a local phenomenon. The darker the macrophage is stained for β-galactosidase, the more it resembles the mature epithelioid cell that Lurie identified with the destruction of the tubercle bacillus ( ). Magnification, ×160. Reprinted with permission from ( ) (see also page 103 in reference ).

Citation: Dannenberg, Jr. A, Converse P. 2011. Pathophysiology and Immunology, p 29-65. In Schlossberg D (ed), Tuberculosis and Nontuberculous Mycobacterial Infections, Sixth Edition. ASM Press, Washington, DC. doi: 10.1128/9781555817138.ch3
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Image of Figure 13.
Figure 13.

Macrophages stained both for β-galactosidase activity and for acid-fast bacilli in a BCG lesion of a rabbit injected intradermally 21 days previously. The macrophage near the center shows negligible β-galactosidase activity. It contains numerous bacilli and has ruptured. Another macrophage (just adjacent) shows high β-galactosidase activity. It contains no bacilli but apparently is ingesting the bacilli released from the ruptured cell. These two cells illustrate how CMI works; i.e., CMI produces locally many highly activated macrophages that can ingest (and destroy) bacilli released from ineffectual macrophages ( ). Several other activated macrophages are also shown in this photograph. Magnification, ×1,600. Reprinted from reference (see also page 102 in reference ).

Citation: Dannenberg, Jr. A, Converse P. 2011. Pathophysiology and Immunology, p 29-65. In Schlossberg D (ed), Tuberculosis and Nontuberculous Mycobacterial Infections, Sixth Edition. ASM Press, Washington, DC. doi: 10.1128/9781555817138.ch3
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References

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1. Abbas, A. K.,, and A. H. Lichtman. 2008. Basic Immunology: Functions and Disorders of the Immune System, 3rd ed. Saunders/Elsevier, Philadelphia, PA.
2. Abdul-Majid, K.-B.,, L. H. Ly,, P. J. Converse,, D. E. Geiman,, D. N. McMurray,, and W. R. Bishai. 2008. Altered cellular infiltration and cytokine levels during early Mycobacterium tuberculosis sigC mutant infection are associated with late-stage disease attenuation and milder immunopathology in mice. BMC Microbiology 8:151.
3. Abe, Y.,, K. Sugisaki,, and A. M. Dannenberg, Jr. 1996. Rabbit vascular endothelial adhesion molecules: ELAM-1 is most elevated in acute inflammation, whereas VCAM-1 and ICAM-1 predominate in chronic inflammation. J. Leukoc. Biol. 60:692703.
4. Abel, B.,, N. Thieblemont,, V. J. Quesniaux,, N. Brown,, J. Mpagi,, K. Miyake,, F. Bihl,, and B. Ryffel. 2002. Toll-like receptor 4 expression is required to control chronic Mycobacterium tuberculosis infection in mice. J. Immunol. 169:31553162.
5. Abou-Zeid, C.,, I. Smith,, J. M. Grange,, T. L. Ratliff,, J. Steele,, and G. A. Rook. 1988. The secreted antigens of Mycobacterium tuberculosis and their relationship to those recognized by the available antibodies. J. Gen. Microbiol. 134:531538.
6. Allison, M. J.,, P. Zappasodi,, and M. P. Lurie. 1962. Host-parasite relationships in natively resistant and susceptible rabbits on quantitative inhalation of tubercle bacilli. Their significance for the nature of genetic resistance. Am. Rev. Respir. Dis. 85:553569.
7. Andersen, P. 2001. TB vaccines: progress and problems. Trends Immunol. 22:160168.
8. Andersen, P. 2007. Tuberculosis vaccines—an update. Nat. Rev. Microbiol. 5:484487.
9. Andersen, P. 2007. Vaccine strategies against latent tuberculosis infection. Trends Microbiol. 15:713.
10. Andersen, P.,, D. Askgaard,, L. Ljungqvist,, J. Bennedsen,, and I. Heron. 1991. Proteins released from Mycobacterium tuberculosis during growth. Infect. Immun. 59:19051910.
11. Ando, M.,, A. M. Dannenberg, Jr.,, M. Sugimoto,, and B. S. Tepper. 1977. Histochemical studies relating the activation of macrophages to the intracellular destruction of tubercle bacilli. Am. J. Pathol. 86:623634.
12. Ando, M. 1973. Macrophage activation in tuberculin reactions of rabbits with primary BCG infection and reinfection. J. Reticuloendothel. Soc. 14:132145.
13. Armstrong, J. A.,, and P. D. Hart. 1971. Response of cultured macrophages to Mycobacterium tuberculosis, with observations on fusion of lysosomes with phagosomes. J. Exp. Med. 134:713740.
14. Austyn, J. M. 1996. New insights into the mobilization and phagocytic activity of dendritic cells. J. Exp. Med. 183:12871292.
15. Balbi, B.,, M. T. Valle,, S. Oddera,, D. Giunti,, F. Manca,, G. A. Rossi,, and L. Allegra. 1993. T-lymphocytes with gamma delta+ V delta 2+ antigen receptors are present in increased proportions in a fraction of patients with tuberculosis or with sarcoidosis. Am. Rev. Respir. Dis. 148:16851690.
16. Banchereau, J.,, and R. M. Steinman. 1998. Dendritic cells and the control of immunity. Nature 392:245252.
17. Barnes, P. F.,, A. B. Bloch,, P. T. Davidson,, and D. E. Snider, Jr. 1991. Tuberculosis in patients with human immunodeficiency virus infection. N. Engl. J. Med. 324:16441650.
18. Barnes, P. F.,, S. J. Fong,, P. J. Brennan,, P. E. Twomey,, A. Mazumder,, and R. L. Modlin. 1990. Local production of tumor necrosis factor and IFN-gamma in tuberculous pleuritis. J. Immunol. 145:149154.
19. Barnes, P. F.,, S. D. Mistry,, C. L. Cooper,, C. Pirmez,, T. H. Rea,, and R. L. Modlin. 1989. Compartmentalization of a CD4+ T lymphocyte subpopulation in tuberculous pleuritis. J. Immunol. 142:11141119.
20. Bean, A. G.,, D. R. Roach,, H. Briscoe,, M. P. France,, H. Korner,, J. D. Sedgwick,, and W. J. Britton. 1999. Structural deficiencies in granuloma formation in TNF gene-targeted mice underlie the heightened susceptibility to aerosol Mycobacterium tuberculosis infection, which is not compensated for by lymphotoxin. J. Immunol. 162:35043511.
21. Beckman, E. M.,, and M. B. Brenner. 1995. MHC class I-like, class II-like and CD1 molecules: distinct roles in immunity. Immunol. Today 16:349352.
22. Beckman, E. M.,, A. Melian,, S. M. Behar,, P. A. Sieling,, D. Chatterjee,, S. T. Furlong,, R. Matsumoto,, J. P. Rosat,, R. L. Modlin,, and S. A. Porcelli. 1996. CD1c restricts responses of mycobacteria-specific T cells. Evidence for antigen presentation by a second member of the human CD1 family. J. Immunol. 157:27952803.
23. Behar, S. M.,, C. C. Dascher,, M. J. Grusby,, C. R. Wang,, and M. B. Brenner. 1999. Susceptibility of mice deficient in CD1D or TAP1 to infection with Mycobacterium tuberculosis. J. Exp. Med. 189:19731980.
24. Behr, M. A.,, and P. M. Small. 1997. Has BCG attenuated to impotence? Nature 389:133134.
25. Behr, M. A.,, and P. M. Small. 1999. A historical and molecular phylogeny of BCG strains. Vaccine 17:915922.
26. Behr, M. A.,, M. A. Wilson,, W. P. Gill,, H. Salamon,, G. K. Schoolnik,, S. Rane,, and P. M. Small. 1999. Comparative genomics of BCG vaccines by whole-genome DNA microarray. Science 284:15201523.
27. Bekker, L. G.,, A. L. Moreira,, A. Bergtold,, S. Freeman,, B. Ryffel,, and G. Kaplan. 2000. Immunopathologic effects of tumor necrosis factor alpha in murine mycobacterial infection are dose dependent. Infect. Immun. 68:69546961.
28. Bellamy, R.,, C. Ruwende,, T. Corrah,, K. P. McAdam,, M. Thursz,, H. C. Whittle,, and A. V. Hill. 1999. Tuberculosis and chronic hepatitis B virus infection in Africans and variation in the vitamin D receptor gene. J. Infect. Dis. 179:721724.
29. Bellamy, R.,, C. Ruwende,, T. Corrah,, K. P. McAdam,, H. C. Whittle,, and A. V. Hill. 1998. Variations in the NRAMP1 gene and susceptibility to tuberculosis in West Africans. N. Engl. J. Med. 338:640644.
30. Bermudez, L. E.,, M. Wu,, and L. S. Young. 1995. Interleukin-12-stimulated natural killer cells can activate human macrophages to inhibit growth of Mycobacterium avium. Infect. Immun. 63:40994104.
31. Boismenu, R.,, and W. L. Havran. 1997. An innate view of gamma delta T cells. Curr. Opin. Immunol. 9:5763.
32. Boom, W. H.,, R. S. Wallis,, and K. A. Chervenak. 1991. Human Mycobacterium tuberculosis-reactive CD4+ T-cell clones: heterogeneity in antigen recognition, cytokine production, and cytotoxicity for mononuclear phagocytes. Infect. Immun. 59:27372743.
33. Brightbill, H. D.,, D. H. Libraty,, S. R. Krutzik,, R. B. Yang,, J. T. Belisle,, J. R. Bleharski,, M. Maitland,, M. V. Norgard,, S. E. Plevy,, S. T. Smale,, P. J. Brennan,, B. R. Bloom,, P. J. Godowski,, and R. L. Modlin. 1999. Host defense mechanisms triggered by microbial lipoproteins through Toll-like receptors. Science 285:732736.
34. Britton, W. J.,, and U. Palendira. 2003. Improving vaccines against tuberculosis. Immunol. Cell Biol. 81:3445.
35. Brodin, P.,, C. Demangel,, and S. T. Cole. 2005. Introduction to functional genomics of the Mycobacterium tuberculosis complex, p. 143–153. In S. T. Cole,, K. D. Eisenach,, D. N. McMurray, and, W. R. Jacobs, Jr. (ed.), Tuberculosis and the Tubercle Bacillus. ASM Press, Washington, DC.
36. Brodin, P.,, K. Eiglmeier,, M. Marmiesse,, A. Billault,, T. Garnier,, S. Niemann,, S. T. Cole,, and R. Brosch. 2002. Bacterial artificial chromosome-based comparative genomic analysis identifies Mycobacterium microti as a natural ESAT-6 deletion mutant. Infect. Immun. 70:55685578.
37. Brooks, J. V.,, A. A. Frank,, M. A. Keen,, J. T. Bellisle,, and I. M. Orme. 2001. Boosting vaccine for tuberculosis. Infect. Immun. 69:27142717.
38. Brosch, R.,, S. V. Gordon,, M. Marmiesse,, P. Brodin,, C. Buchrieser,, K. Eiglmeier,, T. Garnier,, C. Gutierrez,, G. Hewinson,, K. Kremer,, L. M. Parsons,, A. S. Pym,, S. Samper,, D. van Soolingen,, and S. T. Cole. 2002. A new evolutionary scenario for the Mycobacterium tuberculosis complex. Proc. Natl. Acad. Sci. USA 99:36843689.
39. Brown, K. A.,, P. Bedford,, M. Macey,, D. A. McCarthy,, F. Leroy,, A. J. Vora,, A. J. Stagg,, D. C. Dumonde,, and S. C. Knight. 1997. Human blood dendritic cells: binding to vascular endothelium and expression of adhesion molecules. Clin. Exp. Immunol. 107:601607.
40. Brozna, J. P.,, M. Horan,, J. M. Rademacher,, K. M. Pabst,, and M. J. Pabst. 1991. Monocyte responses to sulfatide from Mycobacterium tuberculosis: inhibition of priming for enhanced release of superoxide, associated with increased secretion of interleukin-1 and tumor necrosis factor alpha, and altered protein phosphorylation. Infect. Immun. 59:25422548.
41. Bryk, R.,, C. D. Lima,, H. Erdjument-Bromage,, P. Tempst,, and C. Nathan. 2002. Metabolic enzymes of mycobacteria linked to antioxidant defense by a thioredoxin-like protein. Science 295:10731077.
42. Canetti, G. 1955. The Tubercle Bacillus in the Pulmonary Lesion of Man: Histobacteriology and Its Bearing on the Therapy of Pulmonary Tuberculosis. Springer Publishing Co., New York, NY.
43. Caruso, A. M.,, N. Serbina,, E. Klein,, K. Triebold,, B. R. Bloom,, and J. L. Flynn. 1999. Mice deficient in CD4 T cells have only transiently diminished levels of IFN-gamma, yet succumb to tuberculosis. J. Immunol. 162:54075416.
44. Carvalho, A. C.,, A. Matteelli,, P. Airo,, S. Tedoldi,, C. Casalini,, L. Imberti,, G. P. Cadeo,, A. Beltrame,, and G. Carosi. 2002. γδ T lymphocytes in the peripheral blood of patients with tuberculosis with and without HIV co-infection. Thorax 57:357360.
45. Casanova, J. L.,, and L. Abel. 2002. Genetic dissection of immunity to mycobacteria: the human model. Annu. Rev. Immunol. 20:581620.
46. Centers for Disease Control and Prevention. 2005. Guidelines for preventing the transmission of Mycobacterium tuberculosis in health-care settings. MMWR Morb. Mortal. Wkly. Rep. 54(RR-17):1147.
47. Chaisson, R. E.,, and G. Slutkin. 1989. Tuberculosis and human immunodeficiency virus infection. J. Infect. Dis. 159:96100.
48. Chan, J.,, R. F. Silver,, B. Kampmann,, and R. S. Wallis. 2005. Guidelines for preventing the transmission of Mycobacterium tuberculosis infection, p. 437–449. In S. T. Cole,, K. D. Eisenach,, D. N. McMurray, and, W. R. Jacobs, Jr. (ed.), Tuberculosis and the Tubercle Bacillus. ASM Press, Washington, DC.
49. Chen, Z. W.,, and N. L. Letvin. 2003. Vγ2- Vδ2+ T cells and anti-microbial immune responses. Microbes Infect. 5:491498.
50. Cho, S.,, V. Mehra,, S. Thoma-Uszynski,, S. Stenger,, N. Serbina,, R. J. Mazzaccaro,, J. L. Flynn,, P. F. Barnes,, S. Southwood,, E. Celis,, B. R. Bloom,, R. L. Modlin,, and A. Sette. 2000. Antimicrobial activity of MHC class I-restricted CD8+ T cells in human tuberculosis. Proc. Natl. Acad. Sci. USA 97:1221012215.
51. Cole, S. T.,, K. D. Eisenach,, D. N. McMurray,, and W. R. Jacobs, Jr. (ed.). 2005. Tuberculosis and the Tubercle Bacillus. ASM Press, Washington, DC.
52. Collins, F. M.,, and S. G. Campbell. 1982. Immunity to intracellular bacteria. Vet. Immunol. Immunopathol. 3:566.
53. Collins, H. L.,, and S. H. Kaufmann. 2001. Prospects for better tuberculosis vaccines. Lancet Infect. Dis. 1:2128.
54. Comstock, G. W. 1988. Identification of an effective vaccine against tuberculosis. Am. Rev. Respir. Dis. 138:479480.
55. Comstock, G. W.,, and R. J. O’Brien. 1991. Tuberculosis, p. 745–771. In A. S. Evans and, P. S. Brachman (ed.), Bacterial Infections of Humans: Epidemiology and Control, 2nd ed. Plenum Medical Book Co., New York, NY.
56. Comstock, G. W.,, and S. F. Woolpert. 1978. Tuberculin conversions: true or false? Am. Rev. Respir. Dis. 118:215217.
57. Condos, R.,, W. N. Rom,, and N. W. Schluger. 1997. Treatment of multidrug-resistant pulmonary tuberculosis with interferon-gamma via aerosol. Lancet 349:15131515.
58. Converse, P. J.,, A. M. Dannenberg, Jr.,, J. E. Estep,, K. Sugisaki,, Y. Abe,, B. H. Schofield,, and M. L. Pitt. 1996. Cavitary tuberculosis produced in rabbits by aerosolized virulent tubercle bacilli. Infect. Immun. 64:47764787.
59. Converse, P. J.,, A. M. Dannenberg, Jr.,, T. Shigenaga,, D. N. McMurray,, S. W. Phalen,, J. L. Stanford,, G. A. Rook,, T. Koru-Sengul,, H. Abbey,, J. E. Estep,, and M. L. Pitt. 1998. Pulmonary bovine-type tuberculosis in rabbits: bacillary virulence, inhaled dose effects, tuberculin sensitivity, and Mycobacterium vaccae immunotherapy. Clin. Diagn. Lab. Immunol. 5:871881.
60. Converse, P. J.,, K. D. Eisenach,, S. A. Theus,, E. L. Nuermberger,, S. Tyagi,, L. H. Ly,, D. E. Geiman,, H. Guo,, S. T. Nolan,, N. C. Akar,, L. G. Klinkenberg,, R. Gupta,, S. Lun,, P. C. Karakousis,, G. Lamichhane,, D. N. McMurray,, J. H. Grosset,, and W. R. Bishai. 21 April 2010. The impact of mouse passaging of Mycobacterium tuberculosis strains prior to virulence testing in the mouse and guinea pig models. PLoS One 5(4):e10289. doi:10.1371/journal.pone.0010289.
61. Converse, P. J.,, P. C. Karakousis,, L. G. Klinkenberg,, A. K. Kesavan,, L. H. Ly,, S. S. Allen,, J. H. Grosset,, S. K. Jain,, G. Lamichhane,, Y. C. Manabe,, D. N. McMurray,, E. L. Nuermberger,, and W. R. Bishai. 2009. Role of the dosR-dosS two-component regulatory system in Mycobacterium tuberculosis virulence in three animal models. Infect. Immun. 77:12301237.
62. Cooper, A. M.,, C. D’Souza,, A. A. Frank,, and I. M. Orme. 1997. The course of Mycobacterium tuberculosis infection in the lungs of mice lacking expression of either perforin-or granzyme-mediated cytolytic mechanisms. Infect. Immun. 65:13171320.
63. Cooper, A. M.,, A. Kipnis,, J. Turner,, J. Magram,, J. Ferrante,, and I. M. Orme. 2002. Mice lacking bioactive IL-12 can generate protective, antigen-specific cellular responses to mycobacterial infection only if the IL-12 p40 subunit is present. J. Immunol. 168:13221327.
64. Crowle, A. J. 1988. Imunization against tuberculosis: what kind of vaccine? Infect. Immun. 56:27692773.
65. Daniel, T. M. 1988. Antibody and antigen detection for the immunodiagnosis of tuberculosis: why not? What more is needed? Where do we stand today? J. Infect. Dis. 158:678680.
66. Daniel, T. M. 1989. Rapid diagnosis of tuberculosis: laboratory techniques applicable in developing countries. Rev. Infect. Dis. 11(Suppl. 2): S471S478.
67. Dannenberg, Jr. A. M., 1968. Cellular hypersensitivity and cellular immunity in the pathogenesis of tuberculosis: specificity, systemic and local nature, and associated macrophage enzymes. Bacteriol. Rev. 32:85102.
68. Dannenberg, Jr. A. M., 1978. Pathogenesis of pulmonary tuberculosis in man and animals: protection of personnel against tuberculosis, p. 65–75. In R. Montali (ed.), Mycobacterial Infections of Zoo Animals. Smithsonian Institution Press, Washington, DC.
69. Dannenberg, Jr. A. M., 1984. Pathogenesis of tuberculosis: native and acquired resistance in animals and humans, p. 344–354. In Microbiology—1984. American Society for Microbiology, Washington, DC.
70. Dannenberg, Jr. A. M., 1989. Immune mechanisms in the pathogenesis of pulmonary tuberculosis. Rev. Infect. Dis. 11(Suppl. 2):S369S378.
71. Dannenberg, Jr. A. M., 1990. Controlling tuberculosis: the pathologist’s point of view. Res. Microbiol. 141:192196; discussion, 262263.
72. Dannenberg, Jr. A. M., 1991. Delayed-type hypersensitivity and cell-mediated immunity in the pathogenesis of tuberculosis. Immunol. Today 12:228233.
73. Dannenberg, Jr. A. M., 1993. Immunopathogenesis of pulmonary tuberculosis. Hosp. Pract. (Off. Ed.) 28:5158.
74. Dannenberg, Jr. A. M., 1998. Lurie’s tubercle-count method to test TB vaccine efficacy in rabbits. Front. Biosci. 3:2733.
75. Dannenberg, Jr. A. M., 2001. Pathogenesis of pulmonary Mycobacterium bovis infection: basic principles established by the rabbit model. Tuberculosis (Edinburgh) 81:8796.
76. Dannenberg, Jr. A. M., 2003. Macrophage turnover, division and activation within developing, peak and “healed” tuberculous lesions produced in rabbits by BCG. Tuberculosis (Edinburgh) 83:251260.
77. Dannenberg, Jr. A. M., 2006. Pathogenesis of Human Tuberculosis: Insights from the Rabbit Model. ASM Press, Washington, DC.
78. Dannenberg, Jr. A. M., 2009. Liquefaction and cavity formation in pulmonary TB: a simple method in rabbit skin to test inhibitors. Tuberculosis (Edinburgh) 89:243247.
79. Dannenberg, Jr. A. M., 2010. Perspectives on clinical and pre-clinical testing of new tuberculosis vaccines. Clin. Microbiol. Rev. 23:781794.
80. Dannenberg, Jr., A. M.,, M. S. Burstone,, P. C. Walter,, and J. W. Kinsley. 1963. A histochemical study of phagocytic and enzymatic functions of rabbit mononuclear and polymorpho-nuclear exudate cells and alveolar macrophages. I. Survey and quantitation of enzymes, and states of cellular activation. J. Cell Biol. 17:465486.
81. Dannenberg, Jr., A. M.,, and F. M. Collins. 2001. 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 (Edinburgh) 81:229242.
82. Dannenberg, Jr., A. M.,, O. T. Meyer,, J. R. Esterly,, and T. Kambara. 1968. The local nature of immunity in tuberculosis, illustrated histochemically in dermal BCG lesions. J. Immunol. 100:931941.
83. Reference deleted.
84. Dannenberg, Jr., A. M.,, and G. A. Rook. 1994. Pathogenesis of pulmonary tuberculosis: an interplay of tissue-damaging and macrophage-activating immune responses—dual mechanisms that control bacillary multiplication, p. 459–483. In B. R. Bloom (ed.), Tuberculosis: Pathogenesis, Protection, and Control. ASM Press, Washington, DC.
85. Dannenberg, Jr., A. M.,, and M. Sugimoto. 1976. Liquefaction of caseous foci in tuberculosis. Am. Rev. Respir. Dis. 113:257259.
86. Dannenberg, Jr., A. M.,, and J. Tomashefski. 1998. Pathogenesis of pulmonary tuberculosis, p. 2447–2471. In A. P. Fish-man and, J. A. Elias (ed.), Fishman’s Pulmonary Diseases and Disorders, 3rd ed. McGraw-Hill, Health Professions Division, New York, NY.
87. Darwin, K. H.,, S. Ehrt,, J. C. Gutierrez-Ramos,, N. Weich,, and C. F. Nathan. 2003. The proteasome of Mycobacterium tuberculosis is required for resistance to nitric oxide. Science 302:19631966.
88. Davis, S. L.,, E. L. Nuermberger,, P. K. Um,, C. Vidal,, B. Jedynak,, M. G. Pomper,, W. R. Bishai,, and S. K. Jaim. 2009. Noninvasive pulmonary [18F]-2-fluoro-deoxy-d-glucose positron emission tomography correlates with bactericidal activity of tuberculosis drug treatment. Antimicrob. Agents Chemother. 53:48794884.
89. Demissie, A.,, P. Ravn,, J. Olobo,, T. M. Doherty,, T. Eguale,, M. Geletu,, W. Hailu,, P. Andersen,, and S. Britton. 1999. T-cell recognition of Mycobacterium tuberculosis culture filtrate fractions in tuberculosis patients and their household contacts. Infect. Immun. 67:59675971.
90. Denis, M. 1991. Interferon-gamma-treated murine macrophages inhibit growth of tubercle bacilli via the generation of reactive nitrogen intermediates. Cell. Immunol. 132:150157.
91. Department of Health and Mental Hygiene. 1991. Guidelines for Preventing the Transmission of Tuberculosis in Health-Care Settings. State of Maryland Communicable Diseases Bulletin.
92. Dickinson, J. M.,, M. J. Lefford,, J. Lloyd,, and D. A. Mitchison. 1963. The virulence in the guinea-pig of tubercle bacilli from patients with pulmonary tuberculosis in Hong Kong. Tubercle 44:446451.
93. Dockrell, H. M.,, and Y. Zhang. 2009. A courageous step down the road toward a new tuberculosis vaccine. Am. J. Respir. Clin. Care Med. 179:628629.
94. Doherty, T. M.,, A. Demissie,, J. Olobo,, D. Wolday,, S. Britton,, T. Eguale,, P. Ravn,, and P. Andersen. 2002. Immune responses to the Mycobacterium tuberculosis-specific antigen ESAT-6 signal subclinical infection among contacts of tuberculosis patients. J. Clin. Microbiol. 40:704706.
95. Domenech, P.,, and M. B. Reed. 2009. Rapid and spontaneous loss of phthiocerol dimycocerosate (PDIM) from Mycobacterium tuberculosis grown in vitro: implications for virulence studies. Microbiology 155:35323543.
96. Dorman, S. E.,, C. L. Hatem,, S. Tyagi,, K. Aird,, J. Lopez-Molina,, M. L. Pitt,, B. C. Zook,, A. M. Dannenberg, Jr.,, W. R. Bishai,, and Y. C. Manabe. 2004. Susceptibility to tuberculosis: clues from studies with inbred and outbred New Zealand White rabbits. Infect. Immun. 72:17001705.
97. Dorman, S. E.,, and S. M. Holland. 1998. Mutation in the signal-transducing chain of the interferon-gamma receptor and susceptibility to mycobacterial infection. J. Clin. Investig. 101:23642369.
98. Dowdle, W. R., for the Centers for Disease Control. 1989. A strategic plan for the elimination of tuberculosis in the United States. MMWR Morb. Mortal. Wkly. Rep. 38(Suppl. 3):125.
99. D’Souza, C. D.,, A. M. Cooper,, A. A. Frank,, R. J. Mazzaccaro,, B. R. Bloom,, and I. M. Orme. 1997. An anti-inflammatory role for gamma delta T lymphocytes in acquired immunity to Mycobacterium tuberculosis. J. Immunol. 158:12171221.
100. Ellner, J. J. 1996. Immunosuppression in tuberculosis. Infect. Agents Dis. 5:6272.
101. Ellner, J. J. 1997. Regulation of the human immune response during tuberculosis. J. Lab. Clin. Med. 130:469475.
102. Fenton, M. J.,, L.W. Riley,, and L. S. Schlesinger. 2005. Receptor-mediated recognition of Mycobacterium tuberculosis by host cells, p. 405–426. In S. T. Cole,, K. D. Eisenach,, D. N. McMurray, and, W. R. Jacobs, Jr. (ed.), Tuberculosis and the Tubercle Bacillus. ASM Press, Washington, DC.
103. Filley, E. A.,, H. A. Bull,, P. M. Dowd,, and G. A. Rook. 1992. The effect of Mycobacterium tuberculosis on the susceptibility of human cells to the stimulatory and toxic effects of tumour necrosis factor. Immunology 77:505509.
104. Filley, E. A.,, and G. A. Rook. 1991. Effect of mycobacteria on sensitivity to the cytotoxic effects of tumor necrosis factor. Infect. Immun. 59:25672572.
105. Fine, P. E. 1989. The BCG story: lessons from the past and implications for the future. Rev. Infect. Dis. 11(Suppl. 2): S353S359.
106. Fitzgerald, K. A.,, L. O’Neill,, and A. Gearing. 2001. The Cytokine Factsbook. Elsevier Academic Press, San Diego, CA.
107. Fleischmann, R. D.,, D. Alland,, J. A. Eisen,, L. Carpenter,, O. White,, J. Peterson,, R. DeBoy,, R. Dodson,, M. Gwinn,, D. Haft,, E. Hickey,, J. F. Kolonay,, W. C. Nelson,, L. A. Umayam,, M. Ermolaeva,, S. L. Salzberg,, A. Delcher,, T. Utterback,, J. Weidman,, H. Khouri,, J. Gill,, A. Mikula,, W. Bishai,, W. R. Jacobs, Jr.,, J. C. Venter,, and C. M. Fraser. 2002. Whole-genome comparison of Mycobacterium tuberculosis clinical and laboratory strains. J. Bacteriol. 184:54795490.
108. Flynn, J. L.,, and J. Chan. 2001. Immunology of tuberculosis. Annu. Rev. Immunol. 19:93129.
109. Flynn, J. L.,, M. M. Goldstein,, J. Chan,, K. J. Triebold,, K. Pfeffer,, C. J. Lowenstein,, R. Schreiber,, T. W. Mak,, and B. R. Bloom. 1995. Tumor necrosis factor-alpha is required in the protective immune response against Mycobacterium tuberculosis in mice. Immunity 2:561572.
110. Flynn, J. L.,, M. M. Goldstein,, K. J. Triebold,, B. Koller,, and B. R. Bloom. 1992. Major histocompatibility complex class I-restricted T cells are required for resistance to Mycobacterium tuberculosis infection. Proc. Natl. Acad. Sci. USA 89:1201312017.
111. Flynn, J. L.,, M. M. Goldstein,, K. J. Triebold,, J. Sypek,, S. Wolf,, and B. R. Bloom. 1995. IL-12 increases resistance of BALB/c mice to Mycobacterium tuberculosis infection. J. Immunol. 155:25152524.
112. Fortin, A.,, L. Abel,, J. L. Casanova,, and P. Gros. 2007. Host genetics of mycobacterial diseases in mice and men: forward genetic studies of BCG-osis and tuberculosis. Annu. Rev. Genomics Hum. Genet. 8:163192.
113. Francis, J. 1958. Tuberculosis in Animals and Man: a Study in Comparative Pathology, p. 293–318. Cassell, London, United Kingdom.
114. Frigui, W.,, D. Bottai,, L. Majlessi,, M. Monot,, E. Josselin,, P. Brodin,, T. Garnier,, B. Gicquel,, C. Martin,, C. Leclerc,, S. T. Cole,, and R. Brosch. 2008. Control of M. tuberculosis ESAT-6 secretion and specific T cell recognition by PhoP. PLoS Pathog. 4:e33.
115. Gioia, C.,, C. Agrati,, R. Casetti,, C. Cairo,, G. Borsellino,, L. Battistini,, G. Mancino,, D. Goletti,, V. Colizzi,, L. P. Pucillo,, and F. Poccia. 2002. Lack of CD27-CD45RA-Vγ 9V-δ2+ T cell effectors in immunocompromised hosts and during active pulmonary tuberculosis. J. Immunol. 168:14841489.
116. Gong, J. H.,, M. Zhang,, R. L. Modlin,, P. S. Linsley,, D. Iyer,, Y. Lin,, and P. F. Barnes. 1996. Interleukin-10 downregulates Mycobacterium tuberculosis-induced Th1 responses and CTLA-4 expression. Infect. Immun. 64:913918.
117. Green, S. J.,, C. A. Nacy,, and M. S. Meltzer. 1991. Cytokine-induced synthesis of nitrogen oxides in macrophages: a protective host response to Leishmania and other intracellular pathogens. J. Leukoc. Biol. 50:93103.
118. Greinert, U.,, M. Ernst,, M. Schlaak,, and P. Entzian. 2001. Interleukin-12 as successful adjuvant in tuberculosis treatment. Eur. Respir. J. 17:10491051.
119. Guinn, K. M.,, M. J. Hickey,, S. K. Mathur,, K. L. Zakel,, J. E. Grotzke,, D. M. Lewinsohn,, S. Smith,, and D. R. Sherman. 2004. Individual RD1-region genes are required for export of ESAT-6/CFP-10 and for virulence of Mycobacterium tuberculosis. Mol. Microbiol. 51:359370.
120. Gupta, U. D.,, V. M. Katoch,, and D. N. McMurray. 2007. Current status of TB vaccines. Vaccine 25:37423751.
121. Harshan, K. V.,, and P. R. Gangadharam. 1991. In vivo depletion of natural killer cell activity leads to enhanced multiplication of Mycobacterium avium complex in mice. Infect. Immun. 59:28182821.
122. Hayday, A. C. 2000. Gamma-delta cells: a right time and a right place for a conserved third way of protection. Annu. Rev. Immunol. 18:9751026.
123. Heinzel, A. S.,, J. E. Grotzke,, R. A. Lines,, D. A. Lewinsohn,, A. L. McNabb,, D. N. Streblow,, V. M. Braud,, H. J. Grieser,, J. T. Belisle,, and D. M. Lewinsohn. 2002. HLA-E-dependent presentation of Mtb-derived antigen to human CD8+ T cells. J. Exp. Med. 196:14731481.
124. Hemsworth, G. R.,, and I. Kochan. 1978. Secretion of antimycobacterial fatty acids by normal and activated macrophages. Infect. Immun. 19:170177.
125. Hirsch, C. S.,, R. Hussain,, Z. Toossi,, G. Dawood,, F. Shahid,, and J. J. Ellner. 1996. Cross-modulation by transforming growth factor beta in human tuberculosis: suppression of antigen-driven blastogenesis and interferon gamma production. Proc. Natl. Acad. Sci. USA 93:31933198.
126. Hirsch, C. S.,, Z. Toossi,, J. L. Johnson,, H. Luzze,, L. Ntambi,, P. Peters,, M. McHugh,, A. Okwera,, M. Joloba,, P. Mugyenyi,, R. D. Mugerwa,, P. Terebuh,, and J. J. Ellner. 2001. Augmentation of apoptosis and interferon-gamma production at sites of active Mycobacterium tuberculosis infection in human tuberculosis. J. Infect. Dis. 183:779788.
127. Hirsch, C. S.,, Z. Toossi,, C. Othieno,, J. L. Johnson,, S. K. Schwander,, S. Robertson,, R. S. Wallis,, K. Edmonds,, A. Okwera,, R. Mugerwa,, P. Peters,, and J. J. Ellner. 1999. Depressed T-cell interferon-gamma responses in pulmonary tuberculosis: analysis of underlying mechanisms and modulation with therapy. J. Infect. Dis. 180:20692073.
128. Holland, S. M. 2000. Cytokine therapy of mycobacterial infections. Adv. Intern. Med. 45:431452.
129. Holter, W.,, C. K. Goldman,, L. Casabo,, D. L. Nelson,, W. C. Greene,, and T. A. Waldmann. 1987. Expression of functional IL 2 receptors by lipopolysaccharide and interferon-gamma stimulated human monocytes. J. Immunol. 138:29172922.
130. Horwitz, M. A.,, G. Harth,, B. J. Dillon,, and S. Maslesa-Galic. 2000. Recombinant bacillus Calmette-Guerin (BCG) vaccines expressing the Mycobacterium tuberculosis 30-kDa major secretory protein induce greater protective immunity against tuberculosis than conventional BCG vaccines in a highly susceptible animal model. Proc. Natl. Acad. Sci. USA 97:1385313858.
131. Horwitz, M. A.,, G. Harth,, B. J. Dillon,, and S. Maslesa-Galic. 2005. Enhancing the protective efficacy of Mycobacterium bovis BCG vaccination against tuberculosis by boosting with Mycobacterium tuberculosis major secretory protein. Infect. Immun. 73:46764683.
132. Ito, M.,, N. Kojiro,, T. Ikeda,, T. Ito,, J. Funada,, and T. Kokubu. 1992. Increased proportions of peripheral blood gamma delta T cells in patients with pulmonary tuberculosis. Chest 102:195197.
133. Jaattela, M. 1991. Biologic activities and mechanisms of action of tumor necrosis factor-alpha/cachectin. Lab. Investig. 64:724742.
134. Jain, S. K.,, S. M. Hernandez-Abanto,, Q.-J. Cheng,, P. Singh,, L. H. Ly,, L. G. Klinkenberg,, N. E. Morrison,, P. J. Converse,, E. Nuermberger,, J. Grosset,, D. N. McMurray,, P. C. Karakousis,, G. Lamichhane,, and W. R. Bishai. 2007. Accelerated detection of Mycobacterium tuberculosis genes essential for bacterial survival in guinea pigs, compared with mice. J. Infect. Dis. 195:16341642.
135. Jullien, D.,, S. Stenger,, W. A. Ernst,, and R. L. Modlin. 1997. CD1 presentation of microbial nonpeptide antigens to T cells. J. Clin. Investig. 99:20712074.
136. Kaleab, B.,, T. Ottenoff,, P. Converse,, E. Halapi,, G. Tadesse,, M. Rottenberg,, and R. Kiessling. 1990. Mycobacterial-induced cytotoxic T cells as well as nonspecific killer cells derived from healthy individuals and leprosy patients. Eur. J. Immunol. 20:26512659.
137. Kansas, G. S. 1996. Selectins and their ligands: current concepts and controversies. Blood 88:32593287.
138. Kaplan, G.,, F. A. Post,, A. L. Moreira,, H. Wainwright,, B. N. Kreiswirth,, M. Tanverdi,, B. Mathema,, S. V. Ramaswamy,, G. Walther,, L. M. Steyn,, C. E. Barry III,, and L. G. Bakker. 2003. Mycobacterium tuberculosis growth at the cavity surface: a microenvironment with failed immunity. Infect. Immun. 71:70997108.
139. Kaufmann, S. H. 1988. CD8+ T lymphocytes in intracellular microbial infections. Immunol. Today 9:168174.
140. Kaufmann, S. H. 1989. In vitro analysis of the cellular mechanisms involved in immunity to tuberculosis. Rev. Infect. Dis. 11(Suppl.)2: S448S454.
141. Kaufmann, S. H. 1989. Leprosy and tuberculosis vaccine design. Trop. Med. Parasitol. 40:251257.
142. Kaufmann, S. H. 2001. How can immunology contribute to the control of tuberculosis? Nat. Rev. Immunol. 1:2030.
143. Kaufmann, S. H. 2003. Immunity to intracellular bacteria, p.1229–1261. In W. E. Paul (ed.), Fundamental Immunology, 5th ed. Lippincott Williams & Wilkins, Philadelphia, PA.
144. Keane, J.,, S. Gershon,, R. P. Wise,, E. Mirabile-Levens,, J. Kasznica,, W. D. Schwieterman,, J. N. Siegel,, and M. M. Braun. 2001. Tuberculosis associated with infliximab, a tumor necrosis factor alpha-neutralizing agent. N. Engl. J. Med. 345:10981104.
145. Kindler, V.,, A. P. Sappino,, G. E. Grau,, P. F. Piguet,, and P. Vassalli. 1989. The inducing role of tumor necrosis factor in the development of bactericidal granulomas during BCG infection. Cell 56:731740.
146. Klebanoff, S. 1988. Phagocytic cells: products of oxygen metabolism, p. 391–444. In R. Snyderman,, J. I. Gallin, and, I. M. Goldstein (ed.), Inflammation: Basic Principles and Clinical Correlates. Raven Press, New York, NY.
147. Koch, R. 1891. Fortsetzung der Mitteilungen über ein Heilmittel gegen Tuberkulose. Dtsch. Med. Wochenschr. Jan. 15:101102.
148. Kramnik, I.,, P. Demant,, and B. R. Bloom. 1998. Susceptibility to tuberculosis as a complex genetic trait: analysis using recombinant congenic strains of mice. Novartis Found. Symp. 217:120131; discussion, 132137.
149. Kramnik, I.,, W. F. Dietrich,, P. Demant,, and B. R. Bloom. 2000. Genetic control of resistance to experimental infection with virulent Mycobacterium tuberculosis. Proc. Natl. Acad. Sci. USA 97:85608565.
150. Kumararatne, D. S.,, A. S. Pithie,, P. Drysdale,, J. S. Gaston,, R. Kiessling,, P. B. Iles,, C. J. Ellis,, J. Innes,, and R. Wise. 1990. Specific lysis of mycobacterial antigen-bearing macrophages by class II MHC-restricted polyclonal T cell lines in healthy donors or patients with tuberculosis. Clin. Exp. Immunol. 80:314323.
151. Kupper, T. S. 1990. Immune and inflammatory processes in cutaneous tissues: mechanisms and speculations. J. Clin. Investig. 86:17831789.
152. Kupper, T. S.,, and R. W. Groves. 1995. The interleukin-1 axis and cutaneous inflammation. J. Investig. Dermatol. 105:62S66S.
153. Laal, S.,, and Y. Skeiky. 2005. Immune-based methods, p. 71–83. In S. T. Cole,, K. Eisenach,, D. N. McMurray, and, W. R. Jacobs, Jr. (ed.), Tuberculosis and the Tubercle Bacillus. ASM Press, Washington, DC.
154. Ladel, C. H.,, C. Blum,, A. Dreher,, K. Reifenberg,, and S. H. Kaufmann. 1995. Protective role of gamma/delta T cells and alpha/beta T cells in tuberculosis. Eur. J. Immunol. 25:28772881.
155. Lahn, M.,, A. Kanehiro,, K. Takeda,, J. Terry,, Y. S. Hahn,, M. K. Aydintug,, A. Konowal,, K. Ikuta,, R. L. O’Brien,, E. W. Gelfand,, and W. K. Born. 2002. MHC class I-dependent Vγ4+ pulmonary T cells regulate αβ T cell-independent airway responsiveness. Proc. Natl. Acad. Sci. USA 99:88508855.
156. Lalvani, A.,, R. Brookes,, R. J. Wilkinson,, A. S. Malin,, A. A. Pathan,, P. Andersen,, H. Dockrell,, G. Pasvol,, and A. V. Hill. 1998. Human cytolytic and interferon gamma-secreting CD8+ T lymphocytes specific for Mycobacterium tuberculosis. Proc. Natl. Acad. Sci. USA 95:270275.
157. Laskin, D. L.,, and K. J. Pendino. 1995. Macrophages and inflammatory mediators in tissue injury. Annu. Rev. Pharmacol. Toxicol. 35:655677.
158. Reference deleted.
159. Leonard, E. J.,, and T. Yoshimura. 1990. Human monocyte chemoattractant protein-1 (MCP-1). Immunol. Today 11:97101.
160. Lewinsohn, D. M.,, L. Zhu,, V. J. Madison,, D. C. Dillon,, S. P. Fling,, S. G. Reed,, K. H. Grabstein,, and M. R. Alderson. 2001. Classically restricted human CD8+ T lymphocytes derived from Mycobacterium tuberculosis-infected cells: definition of antigenic specificity. J. Immunol. 166:439446.
161. Li, B.,, M. D. Rossman,, T. Imir,, A. F. Oner-Eyuboglu,, C. W. Lee,, R. Biancaniello,, and S. R. Carding. 1996. Disease-specific changes in gamma-delta T cell repertoire and function in patients with pulmonary tuberculosis. J. Immunol. 157:42224229.
162. Lin, P. L.,, A. Myers,, L. Smith,, C. Bigbee,, M. Bigbee,, C. Fuhrman,, H. Grieser,, I. Chiosea,, N. N. Voitenek,, S. V. Capuano,, E. Klein,, and J. L. Flynn. 2010. Tumor necrosis factor neutralization results in disseminated disease in acute and latent Mycobacterium tuberculosis infection with normal granuloma structure in a cynomolgus macaque model. Arthritis Rheum. 62:340350.
163. Lind, A.,, and M. Ridell. 1984. Immunologically based diagnostic tests: humoral antibody methods, p. 221–248. In G. P. Kubica and, L. G. Wayne (ed.), The Mycobacteria: a Sourcebook. Dekker, New York, NY.
164. Lindner, H.,, E. Holler,, B. Ertl,, G. Multhoff,, M. Schreglmann,, I. Klauke,, S. Schultz-Hector,, and G. Eissner. 1997. Peripheral blood mononuclear cells induce programmed cell death in human endothelial cells and may prevent repair: role of cytokines. Blood 89:19311938.
165. Long, E. R. 1958. The Chemistry and Chemotherapy of Tuberculosis, 3rd ed., p. 106–108 and 122–124. Lippincott Williams & Wilkins, Baltimore, MD.
166. Long, R.,, B. Light,, and J. A. Talbot. 1999. Mycobacteriocidal action of exogenous nitric oxide. Antimicrob. Agents Chemother. 43:403405.
167. Lowrie, D. B. 1990. Is macrophage death on the field of battle essential to victory, or a tactical weakness in immunity against tuberculosis? Clin. Exp. Immunol. 80:301303.
168. Lowrie, D. B. 2003. DNA vaccination: an update. Methods Mol. Med. 87:377390.
169. Lurie, M. B. 1964. Resistance to Tuberculosis: Experimental Studies in Native and Acquired Defensive Mechanisms. Published for the Commonwealth Fund by Harvard University Press, Cambridge, MA.
170. Reference deleted.
171. Lurie, M. B.,, and A. M. Dannenberg, Jr. 1965. Macrophage function in infectious disease with inbred rabbits. Bacteriol. Rev. 29:466476.
172. Lurie, M. B.,, P. Zappasodi,, E. Cardona-Lynch,, and A. M. Dannenberg, Jr. 1952. The response to the intracutaneous inoculation of BCG as an index of native resistance to tuberculosis. J. Immunol. 68:369387.
173. Lurie, M. B.,, P. Zappasodi,, and C. Tickner. 1955. On the nature of genetic resistance to tuberculosis in the light of the host-parasite relationships in natively resistant and susceptible rabbits. Am. Rev. Tuberc. Pulmon. Dis. 72:297329.
174. Lurie, M. B.,, P. Zappasodi,, A. M. Dannenberg, Jr.,, and G. H. Weiss. 1952. On the mechanism of genetic resistance to tuberculosis and its mode of inheritance. Am. J. Hum. Genet. 4:302314.
175. Ly, H. L.,, M. I. Russell,, and D. N. McMurray. 2008. Cytokine profiles in primary and secondary pulmonary granulomas of guinea pigs with tuberculosis. Am. J. Respir. Cell. Mol. Biol. 38:455462.
176. Mackaness, G. B. 1968. The immunology of antituberculous immunity. Am. Rev. Respir. Dis. 97:337344.
177. MacMicking, J.,, Q. W. Xie,, and C. Nathan. 1997. Nitric oxide and macrophage function. Annu. Rev. Immunol. 15:323350.
178. MacMicking, J. D.,, R. J. North,, R. LaCourse,, J. S. Mudgett,, S. K. Shah,, and C. F. Nathan. 1997. Identification of nitric oxide synthase as a protective locus against tuberculosis. Proc. Natl. Acad. Sci. USA 94:52435248.
179. Maini, R.,, E. W. St. Clair,, F. Breedveld,, D. Furst,, J. Kalden,, M. Weisman,, J. Smolen,, P. Emery,, G. Harriman,, M. Feldmann,, and P. Lipsky for the ATTRACT Study Group. 1999. Infliximab (chimeric anti-tumour necrosis factor alpha monoclonal antibody) versus placebo in rheumatoid arthritis patients receiving concomitant methotrexate: a randomised phase III trial. Lancet 354:19321939.
180. Majno, G.,, and I. Joris. 2004. Cells, Tissues, and Disease: Principles of General Pathology, 2nd ed. Oxford University Press, New York, NY.
181. Malik, S.,, and E. Schurr. 2002. Genetic susceptibility to tuberculosis. Clin. Chem. Lab. Med. 40:863868.
182. Manabe, Y. C.,, A. M. Dannenberg, Jr.,, S. K. Tyagi,, C. L. Hatem,, M. Yoder,, S. C. Woolwine,, B. C. Zook,, M. L. Pitt,, and W. R. Bishai. 2003. Different strains of Mycobacterium tuberculosis cause various spectrums of disease in the rabbit model of tuberculosis. Infect. Immun. 71:60046011.
183. Manabe, Y. C.,, C. P. Scott,, and W. R. Bishai. 2002. Naturally attenuated, orally administered Mycobacterium microti as a tuberculosis vaccine is better than subcutaneous Mycobacterium bovis BCG. Infect. Immun. 70:15661570.
184. Manca, C.,, L. Tsenova,, C. E. Barry III,, A. Bergtold,, S. Freeman,, P. A. Haslett,, J. M. Musser,, V. H. Freedman,, and G. Kaplan. 1999. Mycobacterium tuberculosis CDC1551 induces a more vigorous host response in vivo and in vitro, but is not more virulent than other clinical isolates. J. Immunol. 162:67406746.
185. Manca, C.,, L. Tsenova,, A. Bergtold,, S. Freeman,, M. Tovey,, J. M. Musser,, C. E. Barry III,, V. H. Freedman,, and G. Kaplan. 2001. Virulence of a Mycobacterium tuberculosis clinical isolate in mice is determined by failure to induce Th1 type immunity and is associated with induction of IFN-alpha/beta. Proc. Natl. Acad. Sci. USA 98:57525757.
186. Matzinger, P. 2002. The danger model: a renewed sense of self. Science 296:301305.
187. Maw, W. W.,, T. Shimizu,, K. Sato,, and H. Tomioka. 1997. Further study on the roles of the effector molecules of immunosuppressive macrophages induced by mycobacterial infection in expression of their suppressor function against mitogen-stimulated T cell proliferation. Clin. Exp. Immunol. 108:2633.
188. McKinney, J. D.,, K. Honer zu Bentrup,, E. J. Munoz-Elias,, A. Miczak,, B. Chen,, W. T. Chan,, D. Swenson,, J. C. Sacchettini,, W. R. Jacobs, Jr.,, and D. G. Russell. 2000. Persistence of Mycobacterium tuberculosis in macrophages and mice requires the glyoxylate shunt enzyme isocitrate lyase. Nature 406:735738.
189. McShane, H.,, A. A. Pathan,, C. R. Sander,, N. P. Goonetilleke,, H. A. Fletcher,, and A. V. S. Hill. 2005. Boosting BCG with MVA85A: the first candidate subunit vaccine for tuberculosis in clinical trials. Tuberculosis 85:4752.
190. McShane, H.,, A. A. Pathan,, C. R. Sander,, S. M. Keating,, S. C. Gilbert,, K. Huygen,, H. A. Fletcher,, and A. V. Hill. 2004. Recombinant modified vaccinia virus Ankara expressing antigen 85A boosts BCG-primed and naturally acquired antimycobacterial immunity in humans. Nat. Med. 10:12401244.
191. Means, T. K.,, S. Wang,, E. Lien,, A. Yoshimura,, D. T. Golenbock,, and M. J. Fenton. 1999. Human Toll-like receptors mediate cellular activation by Mycobacterium tuberculosis. J. Immunol. 163:39203927.
192. Medina, E.,, and R. J. North. 1998. Resistance ranking of some common inbred mouse strains to Mycobacterium tuberculosis and relationship to major histocompatibility complex haplotype and Nramp1 genotype. Immunology 93:270274.
193. Mendelson, M.,, W. Hanekom,, and G. Kaplan. 2005. Dendritic cells in host immunity to Mycobacterium tuberculosis, p. 451–461. In S. T. Cole,, K. D. Eisenach,, D. N. McMurray, and, W. R. Jacobs, Jr. (ed.), Tuberculosis and the Tubercle Bacillus. ASM Press, Washington, DC.
194. Menzies, D. 1999. Interpretation of repeated tuberculin tests. Boosting, conversion, and reversion. Am. J. Respir. Crit. Care Med. 159:1521.
195. Mitchison, D. A.,, A. L. Bhatia,, S. Radakrishna,, J. B. Selkon,, T. V. Subbaiah,, and J. Wallace. 1961. The virulence in the guinea-pig of tubercle bacilli isolated before treatment from South Indian patients with pulmonary tuberculosis. I. Homogeneity of the investigation and a critique of the virulence test. Bull. W. H. O. 25:285312.
196. Mohan, V. P.,, C. A. Scanga,, K. Yu,, H. M. Scott,, K. E. Tanaka,, E. Tsang,, M. M. Tsai,, J. L. Flynn,, and J. Chan. 2001. Effects of tumor necrosis factor alpha on host immune response in chronic persistent tuberculosis: possible role for limiting pathology. Infect. Immun. 69:18471855.
197. Moncada, S.,, R. M. Palmer,, and E. A. Higgs. 1991. Nitric oxide: physiology, pathophysiology, and pharmacology. Pharmacol. Rev. 43:109142.
198. Moody, D. B.,, T. Ulrichs,, W. Muhlecker,, D. C. Young,, S. S. Gurcha,, E. Grant,, J. P. Rosat,, M. B. Brenner,, C. E. Costello,, G. S. Besra,, and S. A. Porcelli. 2000. CD1c-mediated T-cell recognition of isoprenoid glycolipids in Mycobacterium tuberculosis infection. Nature 404:884888.
199. Müller, I.,, S. P. Cobbold,, H. Waldmann,, and S. H. Kaufmann. 1987. Impaired resistance to Mycobacterium tuberculosis infection after selective in vivo depletion of L3T4+ and Lyt-2+ T cells. Infect. Immun. 55:20372041.
200. Murphy, K.,, P. Travers,, and M. Walport. 2008. Janeway’s Immunobiology, 7th ed. Garland Science, Taylor & Francis Group, New York, NY.
201. Murray, J. F. 2003. Bill Dock and the location of pulmonary tuberculosis: how bed rest might have helped consumption. Am. J. Respir. Crit. Care Med. 168:10291033.
202. Murry, J. P.,, A. K. Pandey,, C. M. Sassetti,, and E. J. Rubin. 2009. Phthiocerol dimycocerosate transport is required for resisting interferon-γ-independent immunity. J. Infect. Dis. 200:774782.
203. Nathan, C. 1991. Mechanisms and modulation of macrophage activation. Behring Inst. Mitt. 88:200207.
204. Reference deleted.
205. Nathan, C. 2002. Points of control in inflammation. Nature 420:846852.
206. Nedeltchev, G.,, T. R. Raghunand,, M. S. Jassal,, S. Lun,, Q. J. Cheng,, and W. R. Bishai. 2009. Extrapulmonary dissemination of Mycobacterium bovis, but not Mycobacterium tuberculosis, in a bronchoscopic rabbit model of cavitary tuberculosis. Infect. Immun. 77:598603.
207. Nolt, D.,, and J. L. Flynn. 2004. Interleukin-12 therapy reduces the number of immune cells and pathology in lungs of mice infected with Mycobacterium tuberculosis. Infect. Immun. 72:29762988.
208. North, R. J. 1974. Cell-mediated immunity of antituberculous immunity in the pathogenesis of tuberculosis: specificity and local nature, and associated macrophage enzymes, p. 418. In R. T. McCluskey and, S. Cohen (ed.), Mechanisms of Cell-Mediated Immunity. Wiley, New York, NY.
209. North, R. J.,, and Y. J. Jung. 2004. Immunity to tuberculosis. Annu. Rev. Immunol. 22:599623.
210. O’Donnell, M. A. 1997. The genetic reconstitution of BCG as a new immunotherapeutic tool. Trends Biotechnol. 15:512517.
211. Ohara, N.,, and T. Yamada. 2001. Recombinant BCG vaccines. Vaccine 19:40894098.
212. Olsen, A. W.,, and P. Andersen. 2003. A novel TB vaccine; strategies to combat a complex pathogen. Immunol. Lett. 85:207211.
213. Orme, I. M.,, and F. M. Collins. 1983. Protection against Mycobacterium tuberculosis infection by adoptive immunotherapy. Requirement for T cell-deficient recipients. J. Exp. Med. 158:7483.
214. Orme, I. M.,, and F. M. Collins. 1984. Adoptive protection of the Mycobacterium tuberculosis-infected lung. Dissociation between cells that passively transfer protective immunity and those that transfer delayed-type hypersensitivity to tuberculin. Cell. Immunol. 84:113120.
215. Orme, I. M.,, D. N. McMurray,, and J. T. Belisle. 2001. Tuberculosis vaccine development: recent progress. Trends Microbiol. 9:115118.
216. Orme, I. M.,, A. D. Roberts,, J. P. Griffin,, and J. S. Abrams. 1993. Cytokine secretion by CD4 T lymphocytes acquired in response to Mycobacterium tuberculosis infection. J. Immunol. 151:518525.
217. Ottenhoff, T. H.,, B. K. Ab,, J. D. Van Embden,, J. E. Thole,, and R. Kiessling. 1988. The recombinant 65-kD heat shock protein of Mycobacterium bovis bacillus Calmette-Guerin/M. tuberculosis is a target molecule for CD4+ cytotoxic T lymphocytes that lyse human monocytes. J. Exp. Med. 168:19471952.
218. Ottenhoff, T. H.,, and R. R. de Vries. 1990. Antigen reactivity and autoreactivity: two sides of the cellular immune response induced by mycobacteria. Curr. Top. Microbiol. Immunol. 155:111121.
219. Pabst, M. J.,, J. M. Gross,, J. P. Brozna,, and M. B. Goren. 1988. Inhibition of macrophage priming by sulfatide from Mycobacterium tuberculosis. J. Immunol. 140:634640.
220. Pan, Y.,, B. S. Yan,, M. Rojas,, Y. V. Shebzukhov,, H. Zhou,, L. Kobzik,, D. E. Higgins,, M. J. Daly,, B. R. Bloom,, and I. Kramnik. 2005. Ipr1 gene mediates innate immunity to tuberculosis. Nature 434:767772.
221. Pieters, J. 2001. Entry and survival of pathogenic mycobacteria in macrophages. Microbes Infect. 3:249255.
222. Pieters, J.,, and H. Ploegh. 2003. Microbiology. Chemical warfare and mycobacterial defense. Science 302:19001902.
223. Pober, J. S.,, and R. S. Cotran. 1990. The role of endothelial cells in inflammation. Transplantation 50:537544.
224. Poole, J.,, and H. Florey. 1970. Chronic inflammation and tuberculosis, p. 1183–1224. In H. Florey (ed.), General Pathology, 4th ed. Saunders, Philadelphia, PA.
225. Porcelli, S. A. 1995. The CD1 family: a third lineage of antigen-presenting molecules. Adv. Immunol. 59:198.
226. Porcelli, S. A.,, and R. L. Modlin. 1999. The CD1 system: antigen-presenting molecules for T cell recognition of lipids and glycolipids. Annu. Rev. Immunol. 17:297329.
227. Porcelli, S. A.,, C. T. Morita,, and R. L. Modlin. 1996. T-cell recognition of non-peptide antigens. Curr. Opin. Immunol. 8:510516.
228. Raulet, D. H. 2003. Natural killer cells, p. 365–391. In W. E. Paul (ed.), Fundamental Immunology, 5th ed. Lippincott Williams & Wilkins, Philadelphia, PA.
229. Ravn, P.,, A. Demissie,, T. Eguale,, H. Wondwosson,, D. Lein,, H. A. Amoudy,, A. S. Mustafa,, A. K. Jensen,, A. Holm,, I. Rosen-krands,, F. Oftung,, J. Olobo,, F. von Reyn,, and P. Andersen. 1999. Human T cell responses to the ESAT-6 antigen from Mycobacterium tuberculosis. J. Infect. Dis. 179:637645.
230. Reggiardo, Z.,, and G. Middlebrook. 1974. Failure of passive serum transfer of immunity against aerogenic tuberculosis in rabbits. Proc. Soc. Exp. Biol. Med. 145:173175.
231. Reggiardo, Z.,, and G. Middlebrook. 1974. Delayed-type hypersensitivity and immunity against aerogenic tuberculosis in guinea pigs. Infect. Immun. 9:815820.
232. Reiling, N.,, C. Holscher,, A. Fehrenbach,, S. Kroger,, C. J. Kirschning,, S. Goyert,, and S. Ehlers. 2002. Cutting edge: Toll-like receptor (TLR)2- and TLR4-mediated pathogen recognition in resistance to airborne infection with Mycobacterium tuberculosis. J. Immunol. 169:34803484.