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Chapter 20 : Cytokine Production in Reinfection BCG Lesions and in Tuberculin Reactions
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
Book DOI:
10.1128/9781555815684
Chapter DOI:
10.1128/9781555815684.ch20
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Abstract:
Reinfection BCG lesions provide a simple model of how tuberculosis vaccines would affect an exogenous infection with virulent tubercle bacilli. Tissue sections of the lesions were prepared, and the types of cells and their cytokine mRNAs and proteins were analyzed by histochemical methods. The cytokines studied were interleukin-1β, macrophage chemoattractant (activating) protein (MCP-1), interleukin-8, and tumor necrosis factor alpha. The most informative findings were with MCP-1, one of the main chemokines attracting mononuclear cells (MN). At 3 h, both the reinfection lesions and the primary lesions contained the same percentage of MN labeled for MCP-1 mRNA. However, the reinfection lesions were 400 to 500 times larger and therefore contained many more of these MN. This high cell number alone would cause the total chemokine production to exceed by far that occurring in the primary lesions. By 1 day, the percentage of MN containing MCP-1 mRNA (and protein) had markedly decreased in the reinfection lesions, but remained high for at least 2 days in the primary lesions, which were beginning to increase in size. The rapid local accumulation of MN (macrophages, dendritic cells, and antigen specific lymphocytes) in the early reinfection BCG lesions seemed to be due to the presence of antibodies that developed during the first BCG infection. The antigen-antibody complexes formed at the site of reinfection evidently produced chemotactic factors that markedly hastened the cell infiltration.
Citation:
Dannenberg, Jr. A.
2006.
Cytokine Production in Reinfection BCG Lesions and in Tuberculin Reactions,
p 312-326.
In
Pathogenesis of Human Pulmonary Tuberculosis.
ASM Press, Washington, DC.
doi: 10.1128/9781555815684.ch20
Figures
Cytokine Production in Reinfection BCG Lesions and in Tuberculin Reactions
Citation:
Dannenberg, Jr. A.
2006.
Cytokine Production in Reinfection BCG Lesions and in Tuberculin Reactions,
p 312-326.
In
Pathogenesis of Human Pulmonary Tuberculosis.
ASM Press, Washington, DC.
doi: 10.1128/9781555815684.ch20
/content/10.1128/9781555815684.ch20.ch20fig01
FIGURE 1
(A) Size of primary and reinfection BCG lesions from 3 h to 42 days in rabbits of Experiment I (3). The reinfected rabbits had been sensitized intradermally by BCG 24 days previously. Note that the reinfection BCG lesions were many times larger than the primary BCG lesions at 3, 12, 24, and 48 h, a fact that was apparently initiated by an antigen-antibody reaction (see chapter 5). Note also that the size of the reinfection BCG lesions reached a second peak at 8 days, whereas the primary lesions reached a similar peak at 12 days. These second peaks were apparently caused by an antigen-specific CMI/DTH reaction (see chapter 5). After the second peaks, the lesions slowly regressed. Each point represents the mean size of the lesions and its standard error. (B) Size of 2-day tuberculin reactions in rabbits of Experiment 1 (3). In the reinfected host, tuberculin sensitivity was highest before challenge. This sensitivity declined thereafter, and no booster effect from the second BCG injection was apparent. In contrast, hosts with primary BCG infections had strong tuberculin sensitivity by 9 days, which tended to remain higher than that present in the reinfected hosts, possibly because the infecting bacilli were not destroyed as readily. Each point represents the mean size of the tuberculin reactions and its standard error. (C) Size of primary and reinfection BCG lesions and tuberculin reactions, each measured from 3 h to 5 days in Experiment II (3). As in Experiment I, the reinfected rabbits were sensitized intradermally by BCG 24 days previously. Note that the reinfection BCG lesions and the tuberculin reactions showed the same pattern, and that the primary BCG lesions remained very small until DTH and CMI started to develop at 4 or 5 days. The tuberculin reactions in the rabbits that had only primary BCG lesions are not shown, because they were small or absent (see panel B). Each point represents the mean size of the lesions and its standard error.
In panels A and C, reinfection BCG lesions versus primary BCG lesions: *P < 0.05 and ** P< 0.01. Reproduced with permission from reference 3. Note that this figure also appears as Fig. 5 in chapter 5.
In panels A and C, reinfection BCG lesions versus primary BCG lesions: *P < 0.05 and ** P< 0.01. Reproduced with permission from reference 3. Note that this figure also appears as Fig. 5 in chapter 5.
10.1128/9781555815684/f0314-01_thmb.gif
10.1128/9781555815684/f0314-01.gif
FIGURE 1
(A) Size of primary and reinfection BCG lesions from 3 h to 42 days in rabbits of Experiment I (3). The reinfected rabbits had been sensitized intradermally by BCG 24 days previously. Note that the reinfection BCG lesions were many times larger than the primary BCG lesions at 3, 12, 24, and 48 h, a fact that was apparently initiated by an antigen-antibody reaction (see chapter 5). Note also that the size of the reinfection BCG lesions reached a second peak at 8 days, whereas the primary lesions reached a similar peak at 12 days. These second peaks were apparently caused by an antigen-specific CMI/DTH reaction (see chapter 5). After the second peaks, the lesions slowly regressed. Each point represents the mean size of the lesions and its standard error. (B) Size of 2-day tuberculin reactions in rabbits of Experiment 1 (3). In the reinfected host, tuberculin sensitivity was highest before challenge. This sensitivity declined thereafter, and no booster effect from the second BCG injection was apparent. In contrast, hosts with primary BCG infections had strong tuberculin sensitivity by 9 days, which tended to remain higher than that present in the reinfected hosts, possibly because the infecting bacilli were not destroyed as readily. Each point represents the mean size of the tuberculin reactions and its standard error. (C) Size of primary and reinfection BCG lesions and tuberculin reactions, each measured from 3 h to 5 days in Experiment II (3). As in Experiment I, the reinfected rabbits were sensitized intradermally by BCG 24 days previously. Note that the reinfection BCG lesions and the tuberculin reactions showed the same pattern, and that the primary BCG lesions remained very small until DTH and CMI started to develop at 4 or 5 days. The tuberculin reactions in the rabbits that had only primary BCG lesions are not shown, because they were small or absent (see panel B). Each point represents the mean size of the lesions and its standard error.
In panels A and C, reinfection BCG lesions versus primary BCG lesions: *P < 0.05 and ** P< 0.01. Reproduced with permission from reference 3. Note that this figure also appears as Fig. 5 in chapter 5.
Citation:
Dannenberg, Jr. A.
2006.
Cytokine Production in Reinfection BCG Lesions and in Tuberculin Reactions,
p 312-326.
In
Pathogenesis of Human Pulmonary Tuberculosis.
ASM Press, Washington, DC.
doi: 10.1128/9781555815684.ch20
/content/10.1128/9781555815684.ch20.ch20fig02
FIGURE 2
Number of mononuclear cells (MN) (A) and PMN (B) per mm2 of tissue section at various times in reinfection BCG lesions, tuberculin reactions, and primary BCG lesions (3). The reinfection BCG lesions and tuberculin reactions show no differences in the density of either cell type, but the primary lesions contain fewer MN per mm2 than the other two at 12 h and at 1 and 2 days. The total number of MN and PMN in each type of lesion can be estimated by combining the data per mm2 (this figure) with the lesion size (Fig. 1). Each point represents the mean and its standard error (see reference 3 for P values). Reproduced with permission from reference 3.
The number of MN and PMN per mm2 in primary BCG lesions at later time periods is shown in Fig. 13 in chapter 6.
The number of MN and PMN per mm2 in primary BCG lesions at later time periods is shown in Fig. 13 in chapter 6.
10.1128/9781555815684/f0316-01_thmb.gif
10.1128/9781555815684/f0316-01.gif
FIGURE 2
Number of mononuclear cells (MN) (A) and PMN (B) per mm2 of tissue section at various times in reinfection BCG lesions, tuberculin reactions, and primary BCG lesions (3). The reinfection BCG lesions and tuberculin reactions show no differences in the density of either cell type, but the primary lesions contain fewer MN per mm2 than the other two at 12 h and at 1 and 2 days. The total number of MN and PMN in each type of lesion can be estimated by combining the data per mm2 (this figure) with the lesion size (Fig. 1). Each point represents the mean and its standard error (see reference 3 for P values). Reproduced with permission from reference 3.
The number of MN and PMN per mm2 in primary BCG lesions at later time periods is shown in Fig. 13 in chapter 6.
Citation:
Dannenberg, Jr. A.
2006.
Cytokine Production in Reinfection BCG Lesions and in Tuberculin Reactions,
p 312-326.
In
Pathogenesis of Human Pulmonary Tuberculosis.
ASM Press, Washington, DC.
doi: 10.1128/9781555815684.ch20
/content/10.1128/9781555815684.ch20.ch20fig03
FIGURE 3
Percentage of MN immunostained for CD4 (A) and CD8 (B) in the three types of lesion (3). At 2 days, the reinfection BCG lesions and tuberculin reactions contained a higher percentage of CD8 cells per mm2 than did the primary lesions, suggesting that tuberculin sensitivity favors the production of cytotoxic T lymphocytes. Note that CD4 cells are much more numerous than CD8 cells (compare the scales on the y axes). The means and their standard errors are shown (see reference 3 for P values). The CD4/CD8 ratios in primary BCG lesions at later times are shown in Table 4 of chapter 6. Reproduced with permission from reference 3. This figure also appears as Fig. 12 in chapter 6.
10.1128/9781555815684/f0317-01_thmb.gif
10.1128/9781555815684/f0317-01.gif
FIGURE 3
Percentage of MN immunostained for CD4 (A) and CD8 (B) in the three types of lesion (3). At 2 days, the reinfection BCG lesions and tuberculin reactions contained a higher percentage of CD8 cells per mm2 than did the primary lesions, suggesting that tuberculin sensitivity favors the production of cytotoxic T lymphocytes. Note that CD4 cells are much more numerous than CD8 cells (compare the scales on the y axes). The means and their standard errors are shown (see reference 3 for P values). The CD4/CD8 ratios in primary BCG lesions at later times are shown in Table 4 of chapter 6. Reproduced with permission from reference 3. This figure also appears as Fig. 12 in chapter 6.
Citation:
Dannenberg, Jr. A.
2006.
Cytokine Production in Reinfection BCG Lesions and in Tuberculin Reactions,
p 312-326.
In
Pathogenesis of Human Pulmonary Tuberculosis.
ASM Press, Washington, DC.
doi: 10.1128/9781555815684.ch20
/content/10.1128/9781555815684.ch20.ch20fig04
FIGURE 4
Percentage of mononuclear cells (MN) labeled for IL-1β mRNA (A), MCP-1 mRNA (B), and IL-8 mRNA (C) in the three types of lesion (3). The percentage of MN containing the three cytokine mRNAs shows early peak levels at 3 h. Then, this percentage of MN rapidly declines in BCG lesions of reinfection and in tuberculin reactions, but remains relatively high in primary BCG lesions at 2 days, especially the percentage containing MCP-1 mRNA. At 2 days, the primary lesions are growing in size, whereas the reinfection lesions and tuberculin reactions are regressing (see Fig. 1C). The means and their standard errors are shown (see reference 3 for P values). Reproduced with permission from reference 3.
10.1128/9781555815684/f0318-01_thmb.gif
10.1128/9781555815684/f0318-01.gif
FIGURE 4
Percentage of mononuclear cells (MN) labeled for IL-1β mRNA (A), MCP-1 mRNA (B), and IL-8 mRNA (C) in the three types of lesion (3). The percentage of MN containing the three cytokine mRNAs shows early peak levels at 3 h. Then, this percentage of MN rapidly declines in BCG lesions of reinfection and in tuberculin reactions, but remains relatively high in primary BCG lesions at 2 days, especially the percentage containing MCP-1 mRNA. At 2 days, the primary lesions are growing in size, whereas the reinfection lesions and tuberculin reactions are regressing (see Fig. 1C). The means and their standard errors are shown (see reference 3 for P values). Reproduced with permission from reference 3.
Citation:
Dannenberg, Jr. A.
2006.
Cytokine Production in Reinfection BCG Lesions and in Tuberculin Reactions,
p 312-326.
In
Pathogenesis of Human Pulmonary Tuberculosis.
ASM Press, Washington, DC.
doi: 10.1128/9781555815684.ch20
/content/10.1128/9781555815684.ch20.ch20fig05
FIGURE 5
Percentage of mononuclear cells (MN) labeled for MCP-1 protein (A) and TNF-α protein (B) in the three types of lesion (3). The percentage of MN containing these two cytokine proteins shows the same pattern as the percentage of MN containing MCP-1 mRNA in Fig. 4, but the early peak at 3 h in the tuberculin-sensitive hosts is much less pronounced. (We did not label TNF-α mRNA in these lesions.) The means and their standard errors are shown (see reference 3 for P values). Reproduced with permission from reference 3.
10.1128/9781555815684/f0320-01_thmb.gif
10.1128/9781555815684/f0320-01.gif
FIGURE 5
Percentage of mononuclear cells (MN) labeled for MCP-1 protein (A) and TNF-α protein (B) in the three types of lesion (3). The percentage of MN containing these two cytokine proteins shows the same pattern as the percentage of MN containing MCP-1 mRNA in Fig. 4, but the early peak at 3 h in the tuberculin-sensitive hosts is much less pronounced. (We did not label TNF-α mRNA in these lesions.) The means and their standard errors are shown (see reference 3 for P values). Reproduced with permission from reference 3.
Citation:
Dannenberg, Jr. A.
2006.
Cytokine Production in Reinfection BCG Lesions and in Tuberculin Reactions,
p 312-326.
In
Pathogenesis of Human Pulmonary Tuberculosis.
ASM Press, Washington, DC.
doi: 10.1128/9781555815684.ch20
/content/10.1128/9781555815684.ch20.ch20fig06
FIGURE 6
Percentage of PMN labeled for IL-1β mRNA (A) and IL-8 mRNA (B) in the three types of lesion (3). Rabbit PMN do not contain MCP-1 mRNA (1–3). Similar to the MN in Fig. 4, the percentage of PMN containing these cytokine mRNAs showed a 3-h peak. Then, the percentage of labeled PMN declined in the reinfection BCG lesions and tuberculin reactions, but remained somewhat elevated in the primary BCG lesions, again similar to the MN in Fig. 4.
Note that at 3 h in reinfection BCG lesions, a much higher percentage of PMN (this figure) than MN (Fig. 4) contained IL-1β mRNA and IL-8 mRNA. At their peaks, IL-1β mRNA was 36% for PMN and 5% for MN, and IL-8 mRNA was 48% for PMN and 8% for MN. Evidently, many PMN produce cytokines as soon as they enter sites of inflammation.
The means and their standard errors are shown (see reference 3 for P values). Reproduced with permission from reference 3.
Note that at 3 h in reinfection BCG lesions, a much higher percentage of PMN (this figure) than MN (Fig. 4) contained IL-1β mRNA and IL-8 mRNA. At their peaks, IL-1β mRNA was 36% for PMN and 5% for MN, and IL-8 mRNA was 48% for PMN and 8% for MN. Evidently, many PMN produce cytokines as soon as they enter sites of inflammation.
The means and their standard errors are shown (see reference 3 for P values). Reproduced with permission from reference 3.
10.1128/9781555815684/f0322-01_thmb.gif
10.1128/9781555815684/f0322-01.gif
FIGURE 6
Percentage of PMN labeled for IL-1β mRNA (A) and IL-8 mRNA (B) in the three types of lesion (3). Rabbit PMN do not contain MCP-1 mRNA (1–3). Similar to the MN in Fig. 4, the percentage of PMN containing these cytokine mRNAs showed a 3-h peak. Then, the percentage of labeled PMN declined in the reinfection BCG lesions and tuberculin reactions, but remained somewhat elevated in the primary BCG lesions, again similar to the MN in Fig. 4.
Note that at 3 h in reinfection BCG lesions, a much higher percentage of PMN (this figure) than MN (Fig. 4) contained IL-1β mRNA and IL-8 mRNA. At their peaks, IL-1β mRNA was 36% for PMN and 5% for MN, and IL-8 mRNA was 48% for PMN and 8% for MN. Evidently, many PMN produce cytokines as soon as they enter sites of inflammation.
The means and their standard errors are shown (see reference 3 for P values). Reproduced with permission from reference 3.
Citation:
Dannenberg, Jr. A.
2006.
Cytokine Production in Reinfection BCG Lesions and in Tuberculin Reactions,
p 312-326.
In
Pathogenesis of Human Pulmonary Tuberculosis.
ASM Press, Washington, DC.
doi: 10.1128/9781555815684.ch20
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