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Chapter 6 : Macrophages and Other Cells in Tuberculous Lesions

Author: Arthur M. Dannenberg, Jr.1
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Affiliations: 1: Center for Tuberculosis Research Departments of Environmental Health Sciences, Molecular Microbiology and Immunology, and Epidemiology, Bloomberg School of Public Health Department of Pathology, School of Medicine Johns Hopkins University, Baltimore, Maryland 21205
Content Type: Monograph
Publication Year: 2006

Category: Clinical Microbiology; Bacterial Pathogenesis

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Macrophages and Other Cells in Tuberculous Lesions, Page 1 of 2

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Abstract:

The main types of cells participating in rabbit tuberculous lesions are dendritic cells (DCs), macrophages, natural killer (NK) cells, lymphocytes, and granulocytes. Follicular DCs and antigen-activated helper T cells interact with B cells for antibody production. The primary acquired immune response to the tubercle bacillus is initiated by DCs that activate T cells. Macrophages can inhibit or kill intracellular tubercle bacilli by means of reactive nitrogen and oxygen intermediates (RNIs and ROIs), to which M. tuberculosis is exquisitely susceptible. Tubercle bacilli can live for months in mouse granulomas without multiplying and without dying. Macrophages are the major cells of the mononuclear phagocyte system. This system is composed of promonocytes in the bone marrow, monocytes in the circulation, and macrophages in the tissues. Active collagenase (an enzyme secreted but not stored in macrophages) was only detected in fluids from peak BCG lesions. T lymphocytes have been divided into various subsets by their CD4 and CD8 surface antigens, by their functions (T helper [Th] cells, regulatory T cells, and cytotoxic T cells), and by the cytokines they produce (Th1 and Th2). Perforin is a protein that can polymerize to form a hole (or pore) in the target cell’s membrane. The eosinophils in rabbit BCG lesions seem to show higher ribonuclease activity than any other cell present. At sites of many infections, mast cell cytokines have been found to enhance the recruitment of T cells. They probably play a similar role in lesions produced by the tubercle bacillus.

Citation: Dannenberg, Jr. A. 2006. Macrophages and Other Cells in Tuberculous Lesions, p 120-152. In Pathogenesis of Human Pulmonary Tuberculosis. ASM Press, Washington, DC. doi: 10.1128/9781555815684.ch6
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Macrophages and Other Cells in Tuberculous Lesions
Citation: Dannenberg, Jr. A. 2006. Macrophages and Other Cells in Tuberculous Lesions, p 120-152. In Pathogenesis of Human Pulmonary Tuberculosis. ASM Press, Washington, DC. doi: 10.1128/9781555815684.ch6
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FIGURE 1
Viable counts and total counts of virulent tubercle bacilli (H37Rv) in the lungs of mice from 9 to 25 weeks after an intravenous infection. After the lungs were homogenized, the viable counts were calculated from the CFU developing on plates containing solid culture medium. The total counts were calculated from the bacilli observed microscopically on spread-smears after acid-fast staining. During this time period, one of the four groups of mice received isoniazid-pyrazinamide (PZA/INH) daily to kill the bacilli.

Note that for untreated mice the average total counts were 0.3 to 0.4 logs higher (2.0 to 2.5 times) than the average viable counts, and that PZA/INH treatment markedly reduced the viable counts but had relatively little effect on the total counts. These findings indicate that (i) most of the dead tubercle bacilli persisted in mouse lungs for many weeks; (ii) most of the live bacilli were in a “dormant” nonmultiplying state, because if they had been multiplying and then had been killed, the total counts (including the dead bacilli) would have increased; and (iii) the good CMI developed by mice activated macrophages sufficiently to prevent the intracellular multiplication of most of the tubercle bacilli. However, at least some of the bacilli were not inhibited by this good CMI, because the disease progressed until the mice succumbed. In other words, not all of the bacilli were dormant, and some bacillary multiplication occurred.

Redrawn from reference 73. These results were confirmed in reference 74 using quantitative real-time PCR technology.
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Image of FIGURE 1
FIGURE 1

Viable counts and total counts of virulent tubercle bacilli (H37Rv) in the lungs of mice from 9 to 25 weeks after an intravenous infection. After the lungs were homogenized, the viable counts were calculated from the CFU developing on plates containing solid culture medium. The total counts were calculated from the bacilli observed microscopically on spread-smears after acid-fast staining. During this time period, one of the four groups of mice received isoniazid-pyrazinamide (PZA/INH) daily to kill the bacilli.

Note that for untreated mice the average total counts were 0.3 to 0.4 logs higher (2.0 to 2.5 times) than the average viable counts, and that PZA/INH treatment markedly reduced the viable counts but had relatively little effect on the total counts. These findings indicate that (i) most of the dead tubercle bacilli persisted in mouse lungs for many weeks; (ii) most of the live bacilli were in a “dormant” nonmultiplying state, because if they had been multiplying and then had been killed, the total counts (including the dead bacilli) would have increased; and (iii) the good CMI developed by mice activated macrophages sufficiently to prevent the intracellular multiplication of most of the tubercle bacilli. However, at least some of the bacilli were not inhibited by this good CMI, because the disease progressed until the mice succumbed. In other words, not all of the bacilli were dormant, and some bacillary multiplication occurred.

Redrawn from reference 73. These results were confirmed in reference 74 using quantitative real-time PCR technology.

Citation: Dannenberg, Jr. A. 2006. Macrophages and Other Cells in Tuberculous Lesions, p 120-152. In Pathogenesis of Human Pulmonary Tuberculosis. ASM Press, Washington, DC. doi: 10.1128/9781555815684.ch6
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FIGURE 2
(A) Size of 48-h tuberculin reactions. (B) Size of BCG lesions. (C) Weighted number of activated β-galactosidase-positive macrophages, just below the surface of the chamber beds of BCG lesions (closed circles) and 72-h tuberculin reactions (open circles). To obtain the weighted number of β-galactosidase-positive macrophages, the number of + cells was multiplied by 1, ++ cells were multiplied by 2, +++ cells were multiplied by 3, and ++++ cells were multiplied by 4, and then the products were added together. Reproduced with permission from reference 108.
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FIGURE 2

(A) Size of 48-h tuberculin reactions. (B) Size of BCG lesions. (C) Weighted number of activated β-galactosidase-positive macrophages, just below the surface of the chamber beds of BCG lesions (closed circles) and 72-h tuberculin reactions (open circles). To obtain the weighted number of β-galactosidase-positive macrophages, the number of + cells was multiplied by 1, ++ cells were multiplied by 2, +++ cells were multiplied by 3, and ++++ cells were multiplied by 4, and then the products were added together. Reproduced with permission from reference 108.

Citation: Dannenberg, Jr. A. 2006. Macrophages and Other Cells in Tuberculous Lesions, p 120-152. In Pathogenesis of Human Pulmonary Tuberculosis. ASM Press, Washington, DC. doi: 10.1128/9781555815684.ch6
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FIGURE 3
Chamber bed of a 32-day BCG lesion. Many darkly staining +++ and ++++ β-galactosidase-positive macrophages are present. A thin proteinaceous layer covers the surface of the chamber bed. Stained with 5-bromo-4-chloro-3-indolyl-β--galactoside, hematoxylin and eosin. Magnification, ×30. Reproduced with permission from reference 108.
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Image of FIGURE 3
FIGURE 3

Chamber bed of a 32-day BCG lesion. Many darkly staining +++ and ++++ β-galactosidase-positive macrophages are present. A thin proteinaceous layer covers the surface of the chamber bed. Stained with 5-bromo-4-chloro-3-indolyl-β--galactoside, hematoxylin and eosin. Magnification, ×30. Reproduced with permission from reference 108.

Citation: Dannenberg, Jr. A. 2006. Macrophages and Other Cells in Tuberculous Lesions, p 120-152. In Pathogenesis of Human Pulmonary Tuberculosis. ASM Press, Washington, DC. doi: 10.1128/9781555815684.ch6
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FIGURE 4
Lysozyme, RNase, DNase, and lactic dehydrogenase (LDH) activities in the chamber fluids of BCG lesions of various ages (closed circles and line graph), 1-day tuberculin reactions (open circles), and normal skin controls (shaded horizontal lines). Lysozyme is both secreted and stored; RNase and DNase are released on cell death and possibly regurgitated, but not secreted; and LDH is released only on cell death.

The chambers were glued to the still intact skin around the area where the epidermis was removed. They were then filled with HEPES culture medium 199, and the fluid within the chambers was collected 48 h later. Note that the highest level of these extracellular hydrolases occurred when tuberculin sensitivity had developed, the BCG lesions were growing to peak size, and the greatest number of activated macrophages was in the chamber bed (see Fig. 1). Reproduced with permission from reference 108.
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FIGURE 4

Lysozyme, RNase, DNase, and lactic dehydrogenase (LDH) activities in the chamber fluids of BCG lesions of various ages (closed circles and line graph), 1-day tuberculin reactions (open circles), and normal skin controls (shaded horizontal lines). Lysozyme is both secreted and stored; RNase and DNase are released on cell death and possibly regurgitated, but not secreted; and LDH is released only on cell death.

The chambers were glued to the still intact skin around the area where the epidermis was removed. They were then filled with HEPES culture medium 199, and the fluid within the chambers was collected 48 h later. Note that the highest level of these extracellular hydrolases occurred when tuberculin sensitivity had developed, the BCG lesions were growing to peak size, and the greatest number of activated macrophages was in the chamber bed (see Fig. 1). Reproduced with permission from reference 108.

Citation: Dannenberg, Jr. A. 2006. Macrophages and Other Cells in Tuberculous Lesions, p 120-152. In Pathogenesis of Human Pulmonary Tuberculosis. ASM Press, Washington, DC. doi: 10.1128/9781555815684.ch6
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FIGURE 5
Tissue section of a 14-day rabbit skin lesion produced by the intradermal injection of 60 × 106 polystyrene latex particles. This lesion showed no inflammation. All of the polystyrene particles were within macrophages staining ++ to ++++ for β-galactosidase. Note that the dermal collagen fibers adjacent to the macrophages are intact, suggesting that no effective collagenase was produced by these cells. A small amount of collagenase was found at 48 h in fluids within chambers placed over the polystyrene lesions, but 2 to 3 times this amount of collagenase was found in chamber fluids placed over 14-day BCG lesions, where the collagen fibers were hydrolyzed (108). Stained with 5-bromo-4-chloro-3-indolyl-β--galactoside, hematoxylin and eosin. Magnification, ×350. Reproduced with permission from reference 108.
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Image of FIGURE 5
FIGURE 5

Tissue section of a 14-day rabbit skin lesion produced by the intradermal injection of 60 × 106 polystyrene latex particles. This lesion showed no inflammation. All of the polystyrene particles were within macrophages staining ++ to ++++ for β-galactosidase. Note that the dermal collagen fibers adjacent to the macrophages are intact, suggesting that no effective collagenase was produced by these cells. A small amount of collagenase was found at 48 h in fluids within chambers placed over the polystyrene lesions, but 2 to 3 times this amount of collagenase was found in chamber fluids placed over 14-day BCG lesions, where the collagen fibers were hydrolyzed (108). Stained with 5-bromo-4-chloro-3-indolyl-β--galactoside, hematoxylin and eosin. Magnification, ×350. Reproduced with permission from reference 108.

Citation: Dannenberg, Jr. A. 2006. Macrophages and Other Cells in Tuberculous Lesions, p 120-152. In Pathogenesis of Human Pulmonary Tuberculosis. ASM Press, Washington, DC. doi: 10.1128/9781555815684.ch6
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FIGURE 6
Estimates of the total amount of each of four enzymes in tissue sections of dermal BCG lesions during their development and healing. The mononuclear cells (mostly macrophages) in these tissue sections were single-stained for acid phosphatase, cathepsin D, esterase and β-galactosidase and were evaluated microscopically at both 35× and 125× magnifications. For quantitation, both the distribution and intensity of the histochemically produced color were taken into account. Then, the total amount of staining was given a rating on a 0 to 9 scale. The standard errors of the means are shown.

Note that the total amount of each enzyme was greatest when the lesions peaked in size (Fig. 2B), and the levels of each enzyme more or less rose and fell in parallel during the development and healing of the lesions. Reproduced with permission from reference 82.
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Image of FIGURE 6
FIGURE 6

Estimates of the total amount of each of four enzymes in tissue sections of dermal BCG lesions during their development and healing. The mononuclear cells (mostly macrophages) in these tissue sections were single-stained for acid phosphatase, cathepsin D, esterase and β-galactosidase and were evaluated microscopically at both 35× and 125× magnifications. For quantitation, both the distribution and intensity of the histochemically produced color were taken into account. Then, the total amount of staining was given a rating on a 0 to 9 scale. The standard errors of the means are shown.

Note that the total amount of each enzyme was greatest when the lesions peaked in size (Fig. 2B), and the levels of each enzyme more or less rose and fell in parallel during the development and healing of the lesions. Reproduced with permission from reference 82.

Citation: Dannenberg, Jr. A. 2006. Macrophages and Other Cells in Tuberculous Lesions, p 120-152. In Pathogenesis of Human Pulmonary Tuberculosis. ASM Press, Washington, DC. doi: 10.1128/9781555815684.ch6
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FIGURE 7
Distribution of mononuclear cells (MN) (mostly macrophages) that single-stained for acid phosphatase, cathepsin D, β-galactosidase, or esterase in developing, peak, and healing dermal BCG lesions. The percentage of MN staining + to ++++ was evaluated microscopically at the edge of the caseous necrotic center, in the viable tissue near this center, and more peripherally in representative high-power fields at ×500 magnification. The standard errors of the means are shown.

Note that macrophages containing β-galactosidase and esterase were more frequent near the caseous center (A and B), and macrophages containing acid phosphatase and cathepsin D were more frequent in the peripheral regions (C). These findings quantitatively demonstrate the “macrolocal” distribution of activated macrophages within tuberculous lesions (see text). Reproduced with permission from reference 82.
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FIGURE 7

Distribution of mononuclear cells (MN) (mostly macrophages) that single-stained for acid phosphatase, cathepsin D, β-galactosidase, or esterase in developing, peak, and healing dermal BCG lesions. The percentage of MN staining + to ++++ was evaluated microscopically at the edge of the caseous necrotic center, in the viable tissue near this center, and more peripherally in representative high-power fields at ×500 magnification. The standard errors of the means are shown.

Note that macrophages containing β-galactosidase and esterase were more frequent near the caseous center (A and B), and macrophages containing acid phosphatase and cathepsin D were more frequent in the peripheral regions (C). These findings quantitatively demonstrate the “macrolocal” distribution of activated macrophages within tuberculous lesions (see text). Reproduced with permission from reference 82.

Citation: Dannenberg, Jr. A. 2006. Macrophages and Other Cells in Tuberculous Lesions, p 120-152. In Pathogenesis of Human Pulmonary Tuberculosis. ASM Press, Washington, DC. doi: 10.1128/9781555815684.ch6
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FIGURE 8
Distribution of activated mononuclear cells (mainly macrophages) in double-stained tissue sections of developing, peak, and healing rabbit dermal BCG lesions. These sections were stained histochemically for pairs of enzymes: one red and one blue. The red enzymes were acid phosphatase, cathepsin D, or red esterase. The blue enzymes were β-galactosidase or blue esterase. The mononuclear cells were counted microscopically at the edge of the caseous necrotic center (A), in the viable tissue near this necrosis (B), and in peripheral areas of the lesion (C).

The length of the bars represents 100% of the mononuclear cells in each area. The cells that stained for only one enzyme of the pair were either red (stippled bars) or blue (hatched bars). The cells that stained for both enzymes of the pair were purple (black bars).

The black bars in column 3 and the mirror-image patterns C:B:A and A:B:C in columns 1 and 2 show that the same macrophage population contained β-galactosidase, red esterase, and blue esterase. Macrophages containing cathepsin D and acid phosphatase had similar distributions (see columns 1 and 2), but since they both stained red, they could not be differentiated in the same tissue section. (The red esterase is from a diazo dye; the blue esterase is from an indolyl dye [82].)

These graphs confirm the microlocal mononuclear cell activation shown in Color Plate 2, i.e., that some macrophages almost always stain for an enzyme different from that of the majority of macrophages in a given area.

Reproduced with permission from reference 82.
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Image of FIGURE 8
FIGURE 8

Distribution of activated mononuclear cells (mainly macrophages) in double-stained tissue sections of developing, peak, and healing rabbit dermal BCG lesions. These sections were stained histochemically for pairs of enzymes: one red and one blue. The red enzymes were acid phosphatase, cathepsin D, or red esterase. The blue enzymes were β-galactosidase or blue esterase. The mononuclear cells were counted microscopically at the edge of the caseous necrotic center (A), in the viable tissue near this necrosis (B), and in peripheral areas of the lesion (C).

The length of the bars represents 100% of the mononuclear cells in each area. The cells that stained for only one enzyme of the pair were either red (stippled bars) or blue (hatched bars). The cells that stained for both enzymes of the pair were purple (black bars).

The black bars in column 3 and the mirror-image patterns C:B:A and A:B:C in columns 1 and 2 show that the same macrophage population contained β-galactosidase, red esterase, and blue esterase. Macrophages containing cathepsin D and acid phosphatase had similar distributions (see columns 1 and 2), but since they both stained red, they could not be differentiated in the same tissue section. (The red esterase is from a diazo dye; the blue esterase is from an indolyl dye [82].)

These graphs confirm the microlocal mononuclear cell activation shown in Color Plate 2, i.e., that some macrophages almost always stain for an enzyme different from that of the majority of macrophages in a given area.

Reproduced with permission from reference 82.

Citation: Dannenberg, Jr. A. 2006. Macrophages and Other Cells in Tuberculous Lesions, p 120-152. In Pathogenesis of Human Pulmonary Tuberculosis. ASM Press, Washington, DC. doi: 10.1128/9781555815684.ch6
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FIGURE 9
Tissue section of a 21-day rabbit dermal BCG lesion stained for β-galactosidase, our marker enzyme for macrophage activation. A group of epithelioid cells with high enzyme activity is seen in the tuberculous granulation tissue that surrounds the lesion’s liquefied caseous center (in the lower right corner of the photograph). Mature epithelioid cells (identified by their rounded appearance) stain the strongest (+++ and ++++) for β-galactosidase. These activated macrophages cluster in the area of the BCG lesion where the bacilli (identified by acid-fast staining) are located. Stained with 5-bromo-4-chloro-3-indolyl-β--galactoside, lightly counterstained with hematoxylin. Magnification, ×200. Reproduced with permission from reference 80.

This picture clearly demonstrates the principle of local immunity, i.e., the bacilli and their products stimulate local lymphocytes to produce cytokines that activate nearby macrophages. Highly activated macrophages are known to contain high concentrations of reactive oxygen and nitrogen intermediates and hydrolytic enzymes that kill or inhibit the tubercle bacillus. Such highly activated macrophages may be harmful to tissues, especially if they die and release their contents. Therefore, the host apparently limits the activation of macrophages to local sites of bacillary lodgement where they are most needed to control the infection.
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Image of FIGURE 9
FIGURE 9

Tissue section of a 21-day rabbit dermal BCG lesion stained for β-galactosidase, our marker enzyme for macrophage activation. A group of epithelioid cells with high enzyme activity is seen in the tuberculous granulation tissue that surrounds the lesion’s liquefied caseous center (in the lower right corner of the photograph). Mature epithelioid cells (identified by their rounded appearance) stain the strongest (+++ and ++++) for β-galactosidase. These activated macrophages cluster in the area of the BCG lesion where the bacilli (identified by acid-fast staining) are located. Stained with 5-bromo-4-chloro-3-indolyl-β--galactoside, lightly counterstained with hematoxylin. Magnification, ×200. Reproduced with permission from reference 80.

This picture clearly demonstrates the principle of local immunity, i.e., the bacilli and their products stimulate local lymphocytes to produce cytokines that activate nearby macrophages. Highly activated macrophages are known to contain high concentrations of reactive oxygen and nitrogen intermediates and hydrolytic enzymes that kill or inhibit the tubercle bacillus. Such highly activated macrophages may be harmful to tissues, especially if they die and release their contents. Therefore, the host apparently limits the activation of macrophages to local sites of bacillary lodgement where they are most needed to control the infection.

Citation: Dannenberg, Jr. A. 2006. Macrophages and Other Cells in Tuberculous Lesions, p 120-152. In Pathogenesis of Human Pulmonary Tuberculosis. ASM Press, Washington, DC. doi: 10.1128/9781555815684.ch6
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FIGURE 10
Tissue section of a 33-day rabbit dermal BCG lesion stained for cytochrome oxidase, an enzyme involved in oxygen metabolism. The large cells are epithelioid cells, similar to those in Fig. 9. The most mature ones with the rounded appearance stain the darkest. In other words, the macrophages most effective in inhibiting the intracellular growth of the tubercle bacillus contained the highest levels of both hydrolytic and oxidative enzymes. The other cells (which we cannot differentiate) are probably small macrophages, dendritic cells, lymphocytes, and plasma cells. Stained with 8-amino-1,2,3,4-tetrahydroquinoline and p-aminodiphenylamine (84) with no counterstain, so the cell nuclei stain lighter than the cytoplasm. Magnification, ×470. Reproduced with permission from reference 81.
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Image of FIGURE 10
FIGURE 10

Tissue section of a 33-day rabbit dermal BCG lesion stained for cytochrome oxidase, an enzyme involved in oxygen metabolism. The large cells are epithelioid cells, similar to those in Fig. 9. The most mature ones with the rounded appearance stain the darkest. In other words, the macrophages most effective in inhibiting the intracellular growth of the tubercle bacillus contained the highest levels of both hydrolytic and oxidative enzymes. The other cells (which we cannot differentiate) are probably small macrophages, dendritic cells, lymphocytes, and plasma cells. Stained with 8-amino-1,2,3,4-tetrahydroquinoline and p-aminodiphenylamine (84) with no counterstain, so the cell nuclei stain lighter than the cytoplasm. Magnification, ×470. Reproduced with permission from reference 81.

Citation: Dannenberg, Jr. A. 2006. Macrophages and Other Cells in Tuberculous Lesions, p 120-152. In Pathogenesis of Human Pulmonary Tuberculosis. ASM Press, Washington, DC. doi: 10.1128/9781555815684.ch6
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FIGURE 11
A generalized presentation of the common types of T cells, i.e., those with αβ antigen receptors (see reference 1). Note that T cells with the CD4 and CD8 surface markers can produce similar cytokines.
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Image of FIGURE 11
FIGURE 11

A generalized presentation of the common types of T cells, i.e., those with αβ antigen receptors (see reference 1). Note that T cells with the CD4 and CD8 surface markers can produce similar cytokines.

Citation: Dannenberg, Jr. A. 2006. Macrophages and Other Cells in Tuberculous Lesions, p 120-152. In Pathogenesis of Human Pulmonary Tuberculosis. ASM Press, Washington, DC. doi: 10.1128/9781555815684.ch6
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FIGURE 12
Percentage of mononuclear cells (MN) (mostly lymphocytes) immunostained for CD4 (A) or CD8 (B) in primary and reinfection BCG lesions and in tuberculin reactions. At 2 days, the reinfection BCG lesions and the tuberculin reactions contained a higher percentage of CD8 cells than did the primary lesions, suggesting that tuberculin sensitivity increases the number of cytotoxic CD8 cells in tuberculous lesions. Note, however, that CD4 cells are always much more numerous than CD8 cells (compare the y axes).

Each point represents the mean of four lesions with its standard error. For reinfection BCG lesions versus primary BCG lesions: *P < 0.05 and **P < 0.01; for tuberculin reactions versus primary BCG lesions: † P < 0.05; and for reinfection BCG lesions versus tuberculin reactions: ‡ P < 0.05 and ‡‡ P < 0.01. Reproduced with permission from reference 119.
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Image of FIGURE 12
FIGURE 12

Percentage of mononuclear cells (MN) (mostly lymphocytes) immunostained for CD4 (A) or CD8 (B) in primary and reinfection BCG lesions and in tuberculin reactions. At 2 days, the reinfection BCG lesions and the tuberculin reactions contained a higher percentage of CD8 cells than did the primary lesions, suggesting that tuberculin sensitivity increases the number of cytotoxic CD8 cells in tuberculous lesions. Note, however, that CD4 cells are always much more numerous than CD8 cells (compare the y axes).

Each point represents the mean of four lesions with its standard error. For reinfection BCG lesions versus primary BCG lesions: *P < 0.05 and **P < 0.01; for tuberculin reactions versus primary BCG lesions: † P < 0.05; and for reinfection BCG lesions versus tuberculin reactions: ‡ P < 0.05 and ‡‡ P < 0.01. Reproduced with permission from reference 119.

Citation: Dannenberg, Jr. A. 2006. Macrophages and Other Cells in Tuberculous Lesions, p 120-152. In Pathogenesis of Human Pulmonary Tuberculosis. ASM Press, Washington, DC. doi: 10.1128/9781555815684.ch6
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FIGURE 13
Mononuclear cells (MN) and granulocytes (PMN) per mm2 of tissue section in BCG lesions at various times during their development and healing. The mononuclear cells were mostly macrophages with some medium and large lymphocytes (and probably some dendritic cells). In the BCG lesions, only the areas that were densely infiltrated with cells were counted. These areas were usually found about one-third of the distance from the edge of the caseous center to the edge of the lesion. PMN were even more numerous nearer the caseous center. At 37 days, the BCG lesions were much smaller, so the total number of cells present was much reduced. Reproduced with permission from reference 163.
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Image of FIGURE 13
FIGURE 13

Mononuclear cells (MN) and granulocytes (PMN) per mm2 of tissue section in BCG lesions at various times during their development and healing. The mononuclear cells were mostly macrophages with some medium and large lymphocytes (and probably some dendritic cells). In the BCG lesions, only the areas that were densely infiltrated with cells were counted. These areas were usually found about one-third of the distance from the edge of the caseous center to the edge of the lesion. PMN were even more numerous nearer the caseous center. At 37 days, the BCG lesions were much smaller, so the total number of cells present was much reduced. Reproduced with permission from reference 163.

Citation: Dannenberg, Jr. A. 2006. Macrophages and Other Cells in Tuberculous Lesions, p 120-152. In Pathogenesis of Human Pulmonary Tuberculosis. ASM Press, Washington, DC. doi: 10.1128/9781555815684.ch6
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FIGURE 14
A tissue section of a 19-day rabbit dermal BCG lesion incubated on a film of RNA for 1 h at 23°C and stained with toluidine blue. Note the “starry sky” appearance representing RNase activity in a percentage of the granulocytes. The cells that have digested the substrate film beneath the tissue section were probably eosinophils, because eosinophils are known to contain high levels of RNase (181, 182), and because most of the PMN (recognized by their multilobed nucleus) were inactive. Magnification, ×180. Reproduced with permission from reference 81.
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Image of FIGURE 14
FIGURE 14

A tissue section of a 19-day rabbit dermal BCG lesion incubated on a film of RNA for 1 h at 23°C and stained with toluidine blue. Note the “starry sky” appearance representing RNase activity in a percentage of the granulocytes. The cells that have digested the substrate film beneath the tissue section were probably eosinophils, because eosinophils are known to contain high levels of RNase (181, 182), and because most of the PMN (recognized by their multilobed nucleus) were inactive. Magnification, ×180. Reproduced with permission from reference 81.

Citation: Dannenberg, Jr. A. 2006. Macrophages and Other Cells in Tuberculous Lesions, p 120-152. In Pathogenesis of Human Pulmonary Tuberculosis. ASM Press, Washington, DC. doi: 10.1128/9781555815684.ch6
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FIGURE 15
A postcapillary venule in a guinea pig contact-sensitivity reaction to dinitrochlorobenzene. Note the preservation of three basophils (arrows): one just outside the venule, one inside the venule, and one between the endothelium and its basement membrane. In this thin GMA tissue section, endothelial cells and pericytes can be easily distinguished by their location. In other words, these thin plastic-embedded tissue sections enable a resolution with light microscopy that approaches the resolution with low-power electron microscopy. In guinea pigs, rabbits, and humans, mast cells and basophils can be easily distinguished by their shape and staining characteristics (164). The tissue specimen was embedded in GMA, cut at 1 to 2 μm, and stained with Giemsa. Magnification, ×790. Reproduced with permission from reference 164.
10.1128/9781555815684/f0143-01_thmb.gif
10.1128/9781555815684/f0143-01.gif
Image of FIGURE 15
FIGURE 15

A postcapillary venule in a guinea pig contact-sensitivity reaction to dinitrochlorobenzene. Note the preservation of three basophils (arrows): one just outside the venule, one inside the venule, and one between the endothelium and its basement membrane. In this thin GMA tissue section, endothelial cells and pericytes can be easily distinguished by their location. In other words, these thin plastic-embedded tissue sections enable a resolution with light microscopy that approaches the resolution with low-power electron microscopy. In guinea pigs, rabbits, and humans, mast cells and basophils can be easily distinguished by their shape and staining characteristics (164). The tissue specimen was embedded in GMA, cut at 1 to 2 μm, and stained with Giemsa. Magnification, ×790. Reproduced with permission from reference 164.

Citation: Dannenberg, Jr. A. 2006. Macrophages and Other Cells in Tuberculous Lesions, p 120-152. In Pathogenesis of Human Pulmonary Tuberculosis. ASM Press, Washington, DC. doi: 10.1128/9781555815684.ch6
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FIGURE 16
Mast cells in a tissue section of normal rabbit skin. The tissue specimen was “cold-embedded” in GMA (174), cut at 1 to 2 μm, and stained with Giemsa. Magnification, ×900.
10.1128/9781555815684/f0143-02_thmb.gif
10.1128/9781555815684/f0143-02.gif
Image of FIGURE 16
FIGURE 16

Mast cells in a tissue section of normal rabbit skin. The tissue specimen was “cold-embedded” in GMA (174), cut at 1 to 2 μm, and stained with Giemsa. Magnification, ×900.

Citation: Dannenberg, Jr. A. 2006. Macrophages and Other Cells in Tuberculous Lesions, p 120-152. In Pathogenesis of Human Pulmonary Tuberculosis. ASM Press, Washington, DC. doi: 10.1128/9781555815684.ch6
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FIGURE 17
Activated fibroblasts (+++ to ++ ++) between collagen fibers in the corium of a healing (6-day) rabbit dermal inflammatory lesion (produced by the topical application of 1% sulfur mustard). These fibroblasts were stained histochemically for the lysosomal enzyme acid phosphatase, which produces the bright red color that appears dark in this black-and-white photograph. The high activation of these fibroblasts is indicated by their large size and the large amount of acid phosphatase that they contain. Normal rabbit skin has relatively few activated fibroblasts (179). Activated fibroblasts produce the new collagen and ground substance associated with healing. A small blood vessel containing erythrocytes can be seen in the lower half of the photograph.

Depicted is a 6-μm “cold-embedded” GMA tissue section, stained histochemically with naphthol AS-BI phosphate and fast red violet LB, and counterstained with hematoxylin. Magnification, ×540. Reproduced with permission from reference 179.
10.1128/9781555815684/f0144-01_thmb.gif
10.1128/9781555815684/f0144-01.gif
Image of FIGURE 17
FIGURE 17

Activated fibroblasts (+++ to ++ ++) between collagen fibers in the corium of a healing (6-day) rabbit dermal inflammatory lesion (produced by the topical application of 1% sulfur mustard). These fibroblasts were stained histochemically for the lysosomal enzyme acid phosphatase, which produces the bright red color that appears dark in this black-and-white photograph. The high activation of these fibroblasts is indicated by their large size and the large amount of acid phosphatase that they contain. Normal rabbit skin has relatively few activated fibroblasts (179). Activated fibroblasts produce the new collagen and ground substance associated with healing. A small blood vessel containing erythrocytes can be seen in the lower half of the photograph.

Depicted is a 6-μm “cold-embedded” GMA tissue section, stained histochemically with naphthol AS-BI phosphate and fast red violet LB, and counterstained with hematoxylin. Magnification, ×540. Reproduced with permission from reference 179.

Citation: Dannenberg, Jr. A. 2006. Macrophages and Other Cells in Tuberculous Lesions, p 120-152. In Pathogenesis of Human Pulmonary Tuberculosis. ASM Press, Washington, DC. doi: 10.1128/9781555815684.ch6
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FIGURE 18
A 1-day dermal inflammatory lesion that was produced in the skin of a rabbit by topical 1% sulfur mustard in methylene chloride. Note the dilated lymphatic vessel and two adjacent small blood vessels containing erythrocytes. This acute chemically induced lesion was grossly edematous, so the lymphatic vessel was dilated from the excess tissue fluid that it was removing. Depicted is a “cold-embedded” (174) 1- to 2- μm GMA tissue section, stained with Giemsa (164). Magnification, ×600.
10.1128/9781555815684/f0144-02_thmb.gif
10.1128/9781555815684/f0144-02.gif
Image of FIGURE 18
FIGURE 18

A 1-day dermal inflammatory lesion that was produced in the skin of a rabbit by topical 1% sulfur mustard in methylene chloride. Note the dilated lymphatic vessel and two adjacent small blood vessels containing erythrocytes. This acute chemically induced lesion was grossly edematous, so the lymphatic vessel was dilated from the excess tissue fluid that it was removing. Depicted is a “cold-embedded” (174) 1- to 2- μm GMA tissue section, stained with Giemsa (164). Magnification, ×600.

Citation: Dannenberg, Jr. A. 2006. Macrophages and Other Cells in Tuberculous Lesions, p 120-152. In Pathogenesis of Human Pulmonary Tuberculosis. ASM Press, Washington, DC. doi: 10.1128/9781555815684.ch6
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Tables

Macrophages and Other Cells in Tuberculous Lesions
Citation: Dannenberg, Jr. A. 2006. Macrophages and Other Cells in Tuberculous Lesions, p 120-152. In Pathogenesis of Human Pulmonary Tuberculosis. ASM Press, Washington, DC. doi: 10.1128/9781555815684.ch6
/content/10.1128/9781555815684.ch06.ch06tab01
TABLE 1
Major cell types involved in specific and nonspecific host defense reactions against the tubercle bacillus a
Generic image for table
TABLE 1

Major cell types involved in specific and nonspecific host defense reactions against the tubercle bacillus a

Citation: Dannenberg, Jr. A. 2006. Macrophages and Other Cells in Tuberculous Lesions, p 120-152. In Pathogenesis of Human Pulmonary Tuberculosis. ASM Press, Washington, DC. doi: 10.1128/9781555815684.ch6
/content/10.1128/9781555815684.ch06.ch06tab02
TABLE 2
β-Galactosidase (β-Gal) activity and the number of acid-fast bacilli seen in immature and mature epithelioid cells in nonnecrotic granulation tissue of dermal BCG lesions a
Generic image for table
TABLE 2

β-Galactosidase (β-Gal) activity and the number of acid-fast bacilli seen in immature and mature epithelioid cells in nonnecrotic granulation tissue of dermal BCG lesions a

Citation: Dannenberg, Jr. A. 2006. Macrophages and Other Cells in Tuberculous Lesions, p 120-152. In Pathogenesis of Human Pulmonary Tuberculosis. ASM Press, Washington, DC. doi: 10.1128/9781555815684.ch6
/content/10.1128/9781555815684.ch06.ch06tab03
TABLE 3
Macrophage activation and 14C-labeled bacillary components within dermal BCG lesions
Generic image for table
TABLE 3

Macrophage activation and 14C-labeled bacillary components within dermal BCG lesions

Citation: Dannenberg, Jr. A. 2006. Macrophages and Other Cells in Tuberculous Lesions, p 120-152. In Pathogenesis of Human Pulmonary Tuberculosis. ASM Press, Washington, DC. doi: 10.1128/9781555815684.ch6
/content/10.1128/9781555815684.ch06.ch06tab04
TABLE 4
Percentage of CD4 and CD8 lymphocytes in the mononuclear cell population of primary BCG lesions during their development and healing a
Generic image for table
TABLE 4

Percentage of CD4 and CD8 lymphocytes in the mononuclear cell population of primary BCG lesions during their development and healing a

Citation: Dannenberg, Jr. A. 2006. Macrophages and Other Cells in Tuberculous Lesions, p 120-152. In Pathogenesis of Human Pulmonary Tuberculosis. ASM Press, Washington, DC. doi: 10.1128/9781555815684.ch6

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