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Chapter 27 : Pathogenesis of Pulmonary Tuberculosis: an Interplay of Tissue-Damaging and Macrophage-Activating Immune Responses—Dual Mechanisms That Control Bacillary Multiplication

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Abstract:

Once the first small caseous tuberculous lesion is established, all subsequent battles occur in a host capable of both tissue damaging and macrophage-activating immune responses. Both tissue-damaging and macrophage-activating immune responses can stop the growth (i.e., multiplication) of tubercle bacilli, because these bacilli do not multiply appreciably in nonliquefied caseous necrotic tissue. Various inflammatory mediators, e.g., clotting factors, eicosanoids, cytokines, hydrolytic enzymes, and reactive oxygen and nitrogen intermediates, are frequently involved in one or both processes. However, the principles described in this chapter are most easily understood if the reader accepts our simplified definitions, namely, that the tissue-damaging hypersensitivity process kills nonactivated macrophages that have allowed tubercle bacilli to multiply within them and that the cell-mediated immunity (CMI) process makes the microbicidal power of macrophages strong enough to kill or inhibit mycobacteria. The macrophage-activating immune response could not be responsible, because the susceptible host develops only weak cell-mediated immunity, and at this stage of the disease, the CMI of the resistant host is not yet fully developed. The majority of pulmonary tuberculous infections of human beings are arrested before they cause clinical disease. Activated macrophages can kill the tubercle bacilli they ingest. Under normal conditions, i.e., before infection begins, most of the alveolar macrophages are nonspecifically activated. Therapeutic agents to prevent liquefaction or to prevent its continuation are greatly needed to treat tuberculosis and limit the spread of this disease to other people.

Citation: Dannenberg, Jr. A, Rook G. 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 Bloom B (ed), Tuberculosis. ASM Press, Washington, DC. doi: 10.1128/9781555818357.ch27
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Image of Figure 1
Figure 1

Changes in the number of human-type tubercle bacilli in the lungs of natively resistant rabbits and natively susceptible rabbits at different intervals after infection by quantitative airborne inhalation. 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 ran parallel. At 4 to 5 weeks, susceptible animals had about 13 times more primary pulmonary tubercles than were present in 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 bacillus, readily occurs in these rabbits ( ). Liquefaction rarely occurs in the susceptible group ( ) because their macrophages apparently develop only low levels of hydrolytic enzymes. (Reprinted with permission from )

Citation: Dannenberg, Jr. A, Rook G. 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 Bloom B (ed), Tuberculosis. ASM Press, Washington, DC. doi: 10.1128/9781555818357.ch27
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Image of Figure 2
Figure 2

A 10-day rabbit pulmonary BCG lesion. In the small caseous center are disintegrated β-galactosidase-negative epithelioid cells containing more than 10 faintly stained tubercle bacilli. Around the small caseous center are viable, young, β-galactosidase-negative macrophages from the bloodstream, which control the fate of the tuberculous lesion. Alveolar macrophages, staining 3 + and 4+ for β-galactosidase (a marker for macrophage activation), have accumulated in the surrounding alveolar area (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 would be released from the initial alveolar macrophages, which in this case had failed to control bacillary multiplication. These bacilli would chemotactically attract from the bloodstream new macrophages, which cannot control the multiplication of tubercle bacilli in their cytoplasm until they become activated by T cells. Magnification, x400. (Photograph reprinted with permission from )

Citation: Dannenberg, Jr. A, Rook G. 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 Bloom B (ed), Tuberculosis. ASM Press, Washington, DC. doi: 10.1128/9781555818357.ch27
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Image of Figure 3
Figure 3

Portion of a tuberculous lesion from one of Lurie's genetically susceptible rabbits 2 weeks after the inhalation of human-type tubercle bacilli. The blood-borne nonactivated macrophages depicted contain numerous (rod-shaped) acid-fast bacilli. Two weeks is near the end of stage II, the stage of symbiosis: the bacilli have grown logarithmically within macrophages with no apparent damage to these cells. Magnification, x850. (Photograph reprinted with permission from )

Citation: Dannenberg, Jr. A, Rook G. 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 Bloom B (ed), Tuberculosis. ASM Press, Washington, DC. doi: 10.1128/9781555818357.ch27
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Figure 4

The sketch of stage I depicts an alveolar macrophage that has ingested and destroyed the two tubercle bacilli in the phagocytic vacuole. The cytoplasm of this macrophage is darkly shaded to depict a high degree of activation, i.e., high levels of lysosomal and oxidative enzymes ( ). The sketch of stage II depicts an early primary tubercle in which tubercle bacilli multiply logarithmically within the macrophages that had emigrated from the bloodstream into the developing lesion. These newly arriving phagocytes are nonactivated and incompetent. The cytoplasm of these macrophages is unshaded to depict the lack of activation. In fact, the phagocytic vacuoles in the cytoplasm of these nonactivated macrophages seem to provide an ideal environment for mycobacterial growth. Stage II is called the stage of symbiosis ( ), since the bacilli are multiplying, the macrophages are accumulating, and neither is destroyed by the other. The sketch of stage III depicts 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 immune response (to the tuberculin-like products of the bacilli) kills the nonactivated macrophages that have allowed the bacilli to grow logarithmically within them ( Fig. 1 and 3 ). The dead and dying macrophages are depicted by fragmented cell membranes. Intact and fragmented bacilli are present, both within macrophages and within the caseum.

Citation: Dannenberg, Jr. A, Rook G. 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 Bloom B (ed), Tuberculosis. ASM Press, Washington, DC. doi: 10.1128/9781555818357.ch27
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Figure 5

The sketch of stage IVa depicts an established tubercle 4 to 5 weeks of age representing that found in one of 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, they again find a favorable intracellular environment in which to multiply. They do so until again the tissue-damaging immune response kills these new bacilli-laden macrophages and the area of caseous necrosis enlarges. This sequence may be repeated many times. The lung 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 AIDS patients.) The sketch of stage IVb depicts an established tubercle 4 to 5 weeks of age representing that found in one of 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), which surrounded the caseum. In such activated macrophages, the bacilli cannot multiply and are eventually destroyed. Such effective (activated) macrophages are produced by T cells and their lymphokines ( Fig. 9 ). 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 even no X-ray evidence of the disease.)

Citation: Dannenberg, Jr. A, Rook G. 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 Bloom B (ed), Tuberculosis. ASM Press, Washington, DC. doi: 10.1128/9781555818357.ch27
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Image of Figure 6
Figure 6

Photograph of stage IVa: a caseous tubercle in the lungs of one of Lurie's susceptible rabbits 5 weeks after the inhalation of human-type tubercle bacilli. Bacilli escaping from the caseous center (left) are ingested by the surrounding nonactivated macrophages, i.e., incompetent immature epithelioid cells (right), where they again find a favorable intracellular environment in which to grow ( Fig. 5 ). Magnification, x660. (Photograph reprinted with permission from )

Citation: Dannenberg, Jr. A, Rook G. 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 Bloom B (ed), Tuberculosis. ASM Press, Washington, DC. doi: 10.1128/9781555818357.ch27
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Figure 7

(A) Multiple caseous foci of hematogenous origin in the lungs of one of Lurie's susceptible rabbits. A large, completely caseous (nonliquefied) primary lesion is present in the middle of the left lung. It was caused by the inhalation of a single unit of one to three virulent bovine-type tubercle bacilli. The hilar nodes were infected by the lymph draining from this primary lesion. Bacilli in the efferent lymph of these infected (caseous) lymph nodes entered the venous circulation to the right side of the heart and then seeded the lungs via branches of the pulmonary artery. Tuberculous lesions were also present in the pleura, in the kidneys, and in the knee joint. (Reprinted with permission from ) (B) Rapidly progressing miliary tuberculosis in an 11-month-old infant. This specimen is the human counterpart of panel A. Most of the multiple caseous areas are of hematogenous origin. The primary lesion is marked by an arrow.

Citation: Dannenberg, Jr. A, Rook G. 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 Bloom B (ed), Tuberculosis. ASM Press, Washington, DC. doi: 10.1128/9781555818357.ch27
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Figure 8

(A) Proliferative type of miliary tubercle in the liver of an 8-month-old male infant. The lesion consists predominantly of a cellular infiltrate composed of macrophages, lymphocytes, plasma cells, and fibroblasts, none of which are distinguishable at this magnification. Part of four Langhans giant cells are seen. They are thought to be formed by several macrophages surrounding a bit of caseous tissue too large for one macrophage to ingest. Hematoxylin and eosin stain. Magnification, xll6. (B) Exudative type of tuberculous lesion in the lung of a 47-year-old black male. Depicted is an area of tuberculous pneumonia. A large proportion of the cellular exudate in the alveolar spaces has undergone caseous necrosis, and the intervening alveolar septa are thickened by infiltrating cells. Hematoxylin and eosin stain. Magnification, x200.

Citation: Dannenberg, Jr. A, Rook G. 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 Bloom B (ed), Tuberculosis. ASM Press, Washington, DC. doi: 10.1128/9781555818357.ch27
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Image of Figure 9
Figure 9

CMI producing local activation of macrophages in the tuberculous lesion. Mononuclear phagocytes are attracted from the bloodstream and are activated locally by lymphocytes and their lymphokines (LK) (probably the most efficient mechanism), by endotoxin-like bacillary products, and also by the ingestion of dead cells and tissue debris. Lymphokines are produced when lymphocytes (mainly T cells) with antigen-specific receptors are stimulated by the bacillus and its products. Only activated macrophages seem capable of destroying the tubercle bacillus. (Reprinted with permission from )

Citation: Dannenberg, Jr. A, Rook G. 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 Bloom B (ed), Tuberculosis. ASM Press, Washington, DC. doi: 10.1128/9781555818357.ch27
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Image of Figure 10
Figure 10

Highly activated (strongly β-galactosidase-positive) macrophages surrounding the caseous center of a 12-day rabbit dermal BCG lesion. This figure illustrates a major aspect of effective CMI, namely, that large numbers of highly activated macrophages accumulate around a caseous focus, so that bacilli released from dead and dying cells will be ingested by competent rather than incompetent cells. Magnification, x115. (Photograph reprinted with permission from )

Citation: Dannenberg, Jr. A, Rook G. 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 Bloom B (ed), Tuberculosis. ASM Press, Washington, DC. doi: 10.1128/9781555818357.ch27
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Image of Figure 11
Figure 11

Macrophages stained for β-galactosidase activity and acid-fast bacilli in a BCG lesion of a rabbit injected intradermally 21 days previously. On the left, one of these macrophages 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 is apparently ingesting the bacilli released from the ruptured cell. This figure illustrates an effective CMI response, namely, highly activated macrophages ingesting (and destroying) bacilli released from ineffectual macrophages. The section was stained with 5-bromo-4-chloroindol-3-yl-β-D-galactopyranoside for β-galactosidases and with carbol fuchsin for acid-fast bacilli and then lightly counterstained with hematoxylin. Magnification, x 1,000. (Photograph reprinted with permission from )

Citation: Dannenberg, Jr. A, Rook G. 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 Bloom B (ed), Tuberculosis. ASM Press, Washington, DC. doi: 10.1128/9781555818357.ch27
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Image of Figure 12
Figure 12

Group of activated macrophages (epithelioid cells) in a 21-day dermal BCG lesion from a rabbit, stained darkly for the lysosomal enzyme |3-galactosidase ( ). Although the perifocal tuberculous granulation tissue contains thousands of macrophages, only those macrophages in locations where tubercle bacilli (and their products) are present seem to become activated and develop the power to destroy the bacillus. In other words, CMI is mainly a localized phenomenon. The darker the macrophage is stained for β-gaIactosidase, the more it resembles Lurie's mature epithelioid cell, which has destroyed tubercle bacilli. The relationship between β-galactosidase activity and destruction of tubercle bacilli was confirmed with C-labeled bacilli and autoradiography ( ). The section was lightly counterstained with hematoxylin. Magnification, X200. (Photograph reprinted with permission from )

Citation: Dannenberg, Jr. A, Rook G. 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 Bloom B (ed), Tuberculosis. ASM Press, Washington, DC. doi: 10.1128/9781555818357.ch27
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Image of Figure 13
Figure 13

Stage V: 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 overwhelm a formerly effective CMI, causing progression of the disease and the destruction of local tissues, including the wall of an adjacent bronchus (illustrated here). The liquefied caseous material is then discharged into the airways, so that the bacilli disseminate to other parts of the lung and to the environment.

Citation: Dannenberg, Jr. A, Rook G. 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 Bloom B (ed), Tuberculosis. ASM Press, Washington, DC. doi: 10.1128/9781555818357.ch27
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Image of Figure 14
Figure 14

Wall of a cavity from one of Lurie's genetically resistant rabbits 8 weeks after the inhalation of human-type tubercle bacilli. The liquefied caseous tissue (right) and liquefying caseous tissue (left) are both swarming with (rod-shaped) acid-fast bacilli. Such bacilli were formerly inhibited in solid caseous tissue, but they now grow profusely in the liquefied menstruum present in the wall of the cavity. Magnification, x600. (Photograph reprinted with permission from )

Citation: Dannenberg, Jr. A, Rook G. 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 Bloom B (ed), Tuberculosis. ASM Press, Washington, DC. doi: 10.1128/9781555818357.ch27
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Image of Figure 15
Figure 15

(A) Cavity in one of Lurie's natively resistant inbred rabbits that had inhaled a single unit of one to three virulent bovine-type tubercle bacilli 9 months previously. The primary lesion eventually formed the cavity, from which large numbers of bacilli infected the larynx and the gut. The tracheobronchial lymph nodes and the kidneys show no overt tuberculous lesions. (Photograph reprinted with permission from ) (B) Single large cavity in the upper lobe of an adult human being. The hilar lymph nodes are only slightly involved, and the rest of the lung has only a few tuberculous lesions.

Citation: Dannenberg, Jr. A, Rook G. 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 Bloom B (ed), Tuberculosis. ASM Press, Washington, DC. doi: 10.1128/9781555818357.ch27
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Image of Figure 16
Figure 16

Left lung of an adult who died of tuberculosis. A large cavity is present in the upper lobe. Bacilli and their tuberculin-like antigens from this cavity caused the caseous bronchopneumonia found in the rest of the lung.

Citation: Dannenberg, Jr. A, Rook G. 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 Bloom B (ed), Tuberculosis. ASM Press, Washington, DC. doi: 10.1128/9781555818357.ch27
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References

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Tables

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Table 1

Basic types of pulmonary tuberculosis

Citation: Dannenberg, Jr. A, Rook G. 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 Bloom B (ed), Tuberculosis. ASM Press, Washington, DC. doi: 10.1128/9781555818357.ch27

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