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Chapter 10 : Macrophage Turnover, Division, and Activation in Tuberculous Lesions

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Abstract:

In rabbit BCG lesions, the turnover of mononuclear cells was most rapid in BCG lesions at 2 to 3 weeks, when the lesion size peaked and tuberculin sensitivity and acquired cellular resistance were well developed. The mononuclear cells were mostly macrophages, with some medium and large lymphocytes and probably some dendritic cells. At this 2- to 3-week peak, more macrophages entered, more died or left, more remained at the site, and more became activated than before or afterward. Before this time, the host had neither delayed-type hypersensitivity nor cell-mediated immunity, so no antigen-specific enhancement of the inflammatory response occurred. After this time, the bacilli and their antigenic products had decreased, so antigen-specific stimuli for cell infiltration and activation were reduced. In “healed” lesions, the mononuclear cell turnover still occurred but was decreased. The continuous entry of live nonactivated macrophages into the viable parts of tuberculous lesions provides fresh intracellular sites where tubercle bacilli can multiply before they are again inhibited by the delayed-type hypersensitivity and cell-mediated immunity of the host. In tuberculosis, bacillary dormancy of long duration can only be present in caseous necrotic tissue where no live host cells exist. In tuberculous lesions produced by BCG in rabbits (and probably those in guinea pigs and humans), macrophages have a continual turnover.

Citation: Dannenberg, Jr. A. 2006. Macrophage Turnover, Division, and Activation in Tuberculous Lesions, p 177-195. In Pathogenesis of Human Pulmonary Tuberculosis. ASM Press, Washington, DC. doi: 10.1128/9781555815684.ch10
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Image of FIGURE 1
FIGURE 1

The total number of [3H]TdR-labeled MN in primary BCG lesions of various ages 5 days after an intravenous injection of [3H]TdR (3HT in figure). (A, age of BCG lesions when [3H]TdR was injected intravenously; B, age of BCG lesions when biopsied. For example, biopsies for the +6 days on the bar graph were taken when the BCG lesions were 11 days of age.)

Most of the [3H]TdR-labeled MN had incorporated [3H]TdR in the bone marrow before they entered the lesions. Therefore, the number of [3H]TdR-labeled MN should be proportional to the number of labeled plus unlabeled MN that entered during the previous 5 days. The number of [3H]TdR-labeled MN was 19 to 34% of the total number of MN within the lesions (2). Note that many more MN entered after DTH was present. Reproduced with permission from reference 2.

The total number of [3H]TdR-labeled MN in BCG lesions was calculated from the lesion size (when measured with calipers), the number of MN per mm2 (counted microscopically), and the percentage of these MN that were [3H]TdR labeled. After the caseous center developed in 1 to 2 weeks, the total number of [3H]TdR-labeled MN in the lesions was less than the number calculated, because caseous necrosis was present (3, 5).

Citation: Dannenberg, Jr. A. 2006. Macrophage Turnover, Division, and Activation in Tuberculous Lesions, p 177-195. In Pathogenesis of Human Pulmonary Tuberculosis. ASM Press, Washington, DC. doi: 10.1128/9781555815684.ch10
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Image of FIGURE 2
FIGURE 2

Rate of appearance and disappearance of [3H]TdR-labeled MN in primary BCG lesions of various ages. [3H]TdR (3HT in figure) was given as a single intravenous pulse to different groups of rabbits at the times indicated at the top of the graph, i.e., when their BCG lesions were –1, +6, +14, or +27 days of age. Note that in each case the percentage of [3H]TdR-labeled MN in the lesions reached its peak about 5 days later, and that about 10 days after the peak these labeled MN had largely disappeared from the lesions (see text). Reproduced with permission from reference 3.

Citation: Dannenberg, Jr. A. 2006. Macrophage Turnover, Division, and Activation in Tuberculous Lesions, p 177-195. In Pathogenesis of Human Pulmonary Tuberculosis. ASM Press, Washington, DC. doi: 10.1128/9781555815684.ch10
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Image of FIGURE 3
FIGURE 3

Percentage of [3H]TdR-labeled MN that survived for 10 days in primary dermal BCG lesions at various times during their growth and regression, specifically, the number of [3H]TdR-labeled MN in the lesions at 15 days (after the intravenous [3H]TdR injection) divided by the number at 5 days, multiplied by 100. (3HT is [3H]TdR.) In this experiment 5 days after the intravenous [3H]TdR pulse, 11 to 33% of the MN in the lesions were labeled with [3H]TdR (3). Ten days later many of these cells had disappeared (died). The percentage that survived during this 10-day period is plotted in this graph (see text). The P values between the upper and lower points are statistically significant (see references 3 and 4). Reproduced with permission from reference 4.

Citation: Dannenberg, Jr. A. 2006. Macrophage Turnover, Division, and Activation in Tuberculous Lesions, p 177-195. In Pathogenesis of Human Pulmonary Tuberculosis. ASM Press, Washington, DC. doi: 10.1128/9781555815684.ch10
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Image of FIGURE 4
FIGURE 4

Changes in [3H]TdR grain counts in [3H]TdR-labeled MN over 22 days. An intravenous pulse of [3H]TdR (3HT in figure) was given when the primary BCG lesions were either 6 or 14 days of age. The grain count made 1 day after the intravenous pulse of [3H]TdR was considered 100%. Halving of this grain count should indicate one cell division. This figure suggests (i) that MN in BCG lesions divided only once (or twice), and (ii) that the presence of DTH reduced the time for this single division to occur, but see the text for another interpretation. Reproduced with permission from reference 2.

Grain counts on MN in BCG lesions of reinfection (with [3H]TdR given at –1 day) resembled the lower curve. Grain counts on MN in primary lesions (with [3H]TdR given at –1 day) resembled the upper curve, but the 1-day primary lesions were small with few cells to count. Grain counts on MN in regressing primary BCG lesions (with [3H]TdR given at +27 days) fell between these two curves.

Citation: Dannenberg, Jr. A. 2006. Macrophage Turnover, Division, and Activation in Tuberculous Lesions, p 177-195. In Pathogenesis of Human Pulmonary Tuberculosis. ASM Press, Washington, DC. doi: 10.1128/9781555815684.ch10
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Image of FIGURE 5a
FIGURE 5a

Percentage of cells labeled with [3H]TdR (3HT in figure) (A) in blood and (B) in 1-day tuberculin traps and in BCG lesions at various times after a single intravenous pulse of [3H]TdR when the BCG lesions were 4 days old. The percentages of [3H]TdR-labeled MN in the blood, traps, and BCG lesions showed similar patterns, which indicates that [3H]TdR incorporation occurred before the MN entered the BCG lesions or soon afterward. It also indicates that the drop in percentage of [3H]TdR-labeled MN in the lesions was at least in part due to a drop in [3H]TdR-labeled MN that continued to enter the BCG lesions from the bloodstream. These rabbits became tuberculin positive when the BCG lesions were 9 days old. Reproduced with permission from reference 5.

Citation: Dannenberg, Jr. A. 2006. Macrophage Turnover, Division, and Activation in Tuberculous Lesions, p 177-195. In Pathogenesis of Human Pulmonary Tuberculosis. ASM Press, Washington, DC. doi: 10.1128/9781555815684.ch10
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Image of FIGURE 5b
FIGURE 5b

Percentage of cells labeled with [3H]TdR (3HT in figure) (A) in blood and (B) in 1-day tuberculin traps and in BCG lesions at various times after a single intravenous pulse of [3H]TdR when the BCG lesions were 4 days old. The percentages of [3H]TdR-labeled MN in the blood, traps, and BCG lesions showed similar patterns, which indicates that [3H]TdR incorporation occurred before the MN entered the BCG lesions or soon afterward. It also indicates that the drop in percentage of [3H]TdR-labeled MN in the lesions was at least in part due to a drop in [3H]TdR-labeled MN that continued to enter the BCG lesions from the bloodstream. These rabbits became tuberculin positive when the BCG lesions were 9 days old. Reproduced with permission from reference 5.

Citation: Dannenberg, Jr. A. 2006. Macrophage Turnover, Division, and Activation in Tuberculous Lesions, p 177-195. In Pathogenesis of Human Pulmonary Tuberculosis. ASM Press, Washington, DC. doi: 10.1128/9781555815684.ch10
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Image of FIGURE 6
FIGURE 6

Percentage of recently entering MN (i.e., [3H]TdR-labeled MN) in primary dermal BCG lesions of various ages that were activated for β-galactosidase. MN enter BCG lesions in an unactivated state. They become activated at a rate that depends on the intensity of the BCG stimulus and on the sensitivity of the host to this stimulus.

The highest percentage of entering MN became activated when [3H]TdR (3HT in figure) was injected intravenously into rabbits with BCG lesions 14 days of age. At this time both the DTH and CMI of the host and the antigenic products of the bacilli were at their height. Means and their standard errors are shown. Reproduced with permission from reference 3.

Citation: Dannenberg, Jr. A. 2006. Macrophage Turnover, Division, and Activation in Tuberculous Lesions, p 177-195. In Pathogenesis of Human Pulmonary Tuberculosis. ASM Press, Washington, DC. doi: 10.1128/9781555815684.ch10
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Image of FIGURE 7
FIGURE 7

Percentage of [3H]TdR-labeled MN in early primary dermal BCG lesions and in early lesions of reinfection. (3HT, [3H]TdR.) A higher percentage of [3H]TdR-labeled MN staining ++ and +++ to ++++ for β-galactosidase was present in reinfection lesions than in primary lesions, indicating that young (recently entering) MN (that incorporated [3H]TdR in the bone marrow) were activated more rapidly when DTH and CMI were present. Reproduced with permission from reference 3. The β-galactosidase substrates used for Fig. 6 and Fig. 7 came from different lots.

Citation: Dannenberg, Jr. A. 2006. Macrophage Turnover, Division, and Activation in Tuberculous Lesions, p 177-195. In Pathogenesis of Human Pulmonary Tuberculosis. ASM Press, Washington, DC. doi: 10.1128/9781555815684.ch10
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Image of FIGURE 8
FIGURE 8

Total number of [3H]TdR-labeled MN (see Fig. 1) that entered early-healing and late-healing dermal BCG lesions in 5 days. The number of [3H]TdR-labeled MN in these lesions, 5 days after the [3H]TdR (3HT in figure) pulse, is proportional to the number of new MN that entered during these 5 days. This figure shows that, even in the final stages of healing, an appreciable number of new MN still enter tuberculous lesions. The difference between the 27-day experiment and the 41- and 63-day experiments was statistically significant. Reproduced with permission from reference 4. (The 27-day experiment presented here was different from the one presented in Fig. 1. Also, the lesion size here was calculated with a 0.52 factor, not the 0.20 factor used in Fig. 1 [see reference 3].)

Citation: Dannenberg, Jr. A. 2006. Macrophage Turnover, Division, and Activation in Tuberculous Lesions, p 177-195. In Pathogenesis of Human Pulmonary Tuberculosis. ASM Press, Washington, DC. doi: 10.1128/9781555815684.ch10
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Image of FIGURE 9
FIGURE 9

Percentage of recently entering MN (i.e., [3H]TdR-labeled MN) that were activated for β-galactosidase in 5 and 8 days in dermal BCG lesions during early, intermediate, and late stages of healing. (3HT, [3H]TdR.) In the late stages of healing, a lower percentage of [3H]TdR-labeled MN was activated, apparently because most of the antigenic bacillary products had been destroyed. Reproduced with permission from reference 4. (The substrate for β-galactosidase used for Fig. 7 and 9 came from the same lot.)

Citation: Dannenberg, Jr. A. 2006. Macrophage Turnover, Division, and Activation in Tuberculous Lesions, p 177-195. In Pathogenesis of Human Pulmonary Tuberculosis. ASM Press, Washington, DC. doi: 10.1128/9781555815684.ch10
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Image of FIGURE 10
FIGURE 10

Size of the tuberculin reactions (top) and percentage of the MN in these tuberculin reactions that stained ++ and +++ for β-galactosidase in primary and reinfection dermal BCG lesions (bottom). (3HT, [3H]TdR.) Note that (i) Old Tuberculin (OT) itself activates considerable numbers of MN, and (ii) after DTH develops, the tuberculin reactions in rabbits with primary BCG lesions are comparable to those in rabbits with reinfection BCG lesions.

We do not know the amount of tuberculin and the amount of other bacillary components within BCG lesions. Therefore, comparisons of the percentages of MN staining for β-galactosidase in these tuberculin reactions with those in the BCG lesions are meaningless. Reproduced with permission from reference 6.

Citation: Dannenberg, Jr. A. 2006. Macrophage Turnover, Division, and Activation in Tuberculous Lesions, p 177-195. In Pathogenesis of Human Pulmonary Tuberculosis. ASM Press, Washington, DC. doi: 10.1128/9781555815684.ch10
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References

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1. Shima, K.,, A. M. Dannenberg, Jr.,, M. Ando,, S. Chandrasekhar,, J. A. Seluzicki, and, J. I. Fabrikant. 1972. Macrophage accumulation, division, maturation, and digestive and microbicidal capacities in tuberculous lesions. I. Studies involving their incorporation of tritiated thymidine and their content of lysosomal enzymes and bacilli. Am. J. Pathol. 67:159180.
2. Ando, M.,, A. M. Dannenberg, Jr., and, K. Shima. 1972. Macrophage accumulation, division, maturation and digestive and microbicidal capacities in tuberculous lesions. II. Rate at which mononuclear cells enter and divide in primary BCG lesions and those of reinfection. J. Immunol. 109:819.
3. Dannenberg, A. M., Jr.,, M. Ando, and, K. Shima. 1972. Macrophage accumulation, division, maturation and digestive and microbicidal capacities in tuberculous lesions. III. The turnover of macrophages and its relation to their activation and antimicrobial immunity in primary BCG lesions and those of reinfection. J. Immunol. 109:11091121.
4. Ando, M., and, A. M. Dannenberg, Jr. 1972. Macrophage accumulation, division, maturation and digestive and microbicidal capacities in tuberculous lesions. IV. Macrophage turnover, lysosomal enzymes and division in healing lesions. Lab. Investig. 27:466472.
5. Tsuda, T.,, A. M. Dannenberg, Jr.,, M. Ando,, H. Abbey, and, A. R. Corrin. 1976. Mononuclear cell turnover in chronic inflammation. Studies on tritiated-thymidine-labeled cells in blood, tuberculin traps and dermal BCG lesions of rabbits. Am. J. Pathol. 83:255268.
6. Ando, M. 1973. Macrophage activation in tuber-culin reactions of rabbits with primary BCG infection and reinfection. J. Reticuloendothel. Soc. 14:132145.
7. Dannenberg, A. M., Jr.,, M. Sugimoto,, L. P. Fay, and, A. L. Massaquoi. 1976. In vivo labeling effectiveness of tritiated thymidine of high and low specific activities in rabbits. Radiat. Res. 67:98103.
8. Ando, M.,, A. M. Dannenberg, Jr.,, E. Courtade, and, K. Shima. 1976. Turnover of tritiated-thymi-dine-labeled mononuclear cells in tuberculous lesions of rabbits. A comparison of primary dermal BCG lesions and those of reinfection. Proc. Soc. Exp. Biol. Med. 151:491494.
9. Chandrasekhar, S.,, K. Shima,, A. M. Dannenberg, Jr.,, T. Kambara,, J. I. Fabrikant, and, W. G. Roessler. 1971. Radiation, infection and macrophage function. IV. The effect of radiation on the proliferative abilities of mononuclear phagocytes in tuberculous lesions of rabbits. Infect. Immun. 3:254259.
10. Dannenberg, A. M., Jr. 2003. Macrophage turnover, division and activation within developing, peak and “healed” tuberculous lesions produced in rabbits by BCG. Tuberculosis 83:251260.
11. van Furth, R. 1970. Origins and kinetics of monocytes and macrophages. Semin. Hematol. 7:125141.
12. Virolainen, M. 1968. Hematopoietic origin of macrophages as studied by chromosome markers in mice. J. Exp. Med. 127:943951.
13. Volkman, A. 1970. The origin and fate of the monocyte. Ser. Haematol. 3:6292.
14. Fabrikant, J. I.,, C. L. Wisseman III, and, M. J. Vitak. 1969. The kinetics of cellular proliferation in normal and malignant tissues. II. An in vitro method for incorporation of tritiated thymi-dine in human tissues. Radiology 92:13091320.
15. Dannenberg, A. M., Jr.,, 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.
16. Dannenberg, A. M., Jr. 1968. Cellular hyper-sensitivity and cellular immunity in the pathogenesis of tuberculosis: specificity, systemic and local nature, and associated macrophage enzymes. Bacteriol. Rev. 32:85102.
17. 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.
18. Cleaver, J. E. 1967. Thymidine Metabolism and Cell Kinetics. Frontiers of Biology, vol. 6. North-Holland Publishing Company, Amsterdam, The Netherlands.
19. Spector, W. G. 1969. The granulomatous inflammatory exudate. Int. Rev. Exp. Pathol. 8:155.
20. Ryan, G. B., and, W. G. Spector. 1970. Macrophage turnover in inflamed connective tissue. Proc. R. Soc. (Biol.) 175:269292.
21. Pearson, B.,, P. L. Wolf, and, J. Vazquez. 1963. A comparative study of a series of new indolyl compounds to localize β-galactosidase in tissues. Lab. Investig. 12:12491259.
22. Yarborough, D. J.,, O. T. Meyer,, A. M. Dannenberg, Jr., and, B. Pearson. 1967. Histo-chemistry of macrophage hydrolases. III. Studies on β-galactosidase, β-glucuronidase and aminopeptidase with indolyl and naphthyl substrates. J. Reticuloendothel. Soc. 4:390408.
23. 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.
24. Lurie, M. B. 1932. The correlation between the histological changes and the fate of living tubercle bacilli in the organs of tuberculous rabbits. J. Exp. Med. 55:3154.
25. Lurie, M. B. 1964. Resistance to Tuberculosis: Experimental Studies in Native and Acquired Defensive Mechanisms. Harvard University Press, Cambridge, Mass.
26. Majno, G., and, I. Joris. 2004. Cells, Tissues, and Disease. Principles of General Pathology, 2nd ed. Oxford University Press, New York, N.Y.
27. Dannenberg, A. M., Jr. 1993. Immunopatho-genesis of pulmonary tuberculosis. Hosp. Pract. 28:3340. (Off. ed. 51–58.)
28. Dannenberg, A. M., Jr. 2001. Pathogenesis of pulmonary Mycobacterium bovis infection: basic principles established by the rabbit model. Tuberculosis 81:8796.
29. Dannenberg, A. M., Jr., 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 81:229242.

Tables

Generic image for table
TABLE 1

Comparison of in vitro and in vivo [3H]TdR-labeling of MN in dermal BCG lesions a

Citation: Dannenberg, Jr. A. 2006. Macrophage Turnover, Division, and Activation in Tuberculous Lesions, p 177-195. In Pathogenesis of Human Pulmonary Tuberculosis. ASM Press, Washington, DC. doi: 10.1128/9781555815684.ch10
Generic image for table
TABLE 2

In vitro[3H]TdR labeling of dermal BCG lesions indicates that intracellular tubercle bacilli do not stimulate mononuclear cell (MN) division a

Citation: Dannenberg, Jr. A. 2006. Macrophage Turnover, Division, and Activation in Tuberculous Lesions, p 177-195. In Pathogenesis of Human Pulmonary Tuberculosis. ASM Press, Washington, DC. doi: 10.1128/9781555815684.ch10
Generic image for table
TABLE 3

[3H]TdR grain counts in [3H]TdR-positive β-galactosidase-positive macrophages in primary and reinfection dermal BCG lesions a

Citation: Dannenberg, Jr. A. 2006. Macrophage Turnover, Division, and Activation in Tuberculous Lesions, p 177-195. In Pathogenesis of Human Pulmonary Tuberculosis. ASM Press, Washington, DC. doi: 10.1128/9781555815684.ch10

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