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Chapter 19 : Cytokine Production in Primary BCG Lesions

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Cytokine Production in Primary BCG Lesions, Page 1 of 2

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Abstract:

A sequential histochemical study of cytokines in developing and healing rabbit tuberculous (BCG) lesions is described in this chapter. In tissue sections, interleukin-1β (IL-1β), tumor necrosis factor alpha (TNF- α), macrophage chemoattractant (activating) protein 1 (MCP-1), and IL-8 are evaluated for cytokine mRNA by in situ hybridization techniques and for cytokine protein by immunohistochemical techniques. In tissue homogenates, gamma interferon (IFN-γ) mRNA was evaluated by reverse transcription-PCR. In the BCG lesions, the percentage of mononuclear cells that contained the mRNAs of these cytokines showed a biphasic pattern. Mononuclear cells containing IL-1β and IL-8 mRNAs were more numerous surrounding the caseous center. These cytokines evidently recruited the polymorphonuclear leukocytes that were common in this location. Mononuclear cells containing MCP-1 mRNA were more numerous in the outer third of the lesion where new macrophages and lymphocytes were being recruited. Both the nonspecific and antigen-specific cytokine responses of BCG vaccines are evidently synergistic. The early nonspecific cytokine (chemokine) response causes a local accumulation of antigen-presenting cells and lymphocytes, which explains, at least in part, why tubercle bacilli are good immunological adjuvants. This adjuvant effect should be considered in developing improved vaccines for the prevention of tuberculosis, because vaccines producing a strong early nonspecific cytokine (chemokine) response should be more immunogenic than vaccines with similar antigens producing a weak response.

Citation: Dannenberg, Jr. A. 2006. Cytokine Production in Primary BCG Lesions, p 301-311. In Pathogenesis of Human Pulmonary Tuberculosis. ASM Press, Washington, DC. doi: 10.1128/9781555815684.ch19
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Figures

Image of FIGURE 1a
FIGURE 1a

The percentage of mononuclear cells labeled for IL-1β (A), TNF-α (B), MCP-1 (C), and IL-8 (D) mRNAs in BCG lesions at various times during their development and regression. Note the biphasic pattern of these cytokine mRNAs. The first peak is due to nonspecific irritation by the injected BCG. The second peak is probably due to the development of antigen-specific immunity. The means and their standard errors are shown. Reproduced with permission from reference 11.

Citation: Dannenberg, Jr. A. 2006. Cytokine Production in Primary BCG Lesions, p 301-311. In Pathogenesis of Human Pulmonary Tuberculosis. ASM Press, Washington, DC. doi: 10.1128/9781555815684.ch19
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Image of FIGURE 1b
FIGURE 1b

The percentage of mononuclear cells labeled for IL-1β (A), TNF-α (B), MCP-1 (C), and IL-8 (D) mRNAs in BCG lesions at various times during their development and regression. Note the biphasic pattern of these cytokine mRNAs. The first peak is due to nonspecific irritation by the injected BCG. The second peak is probably due to the development of antigen-specific immunity. The means and their standard errors are shown. Reproduced with permission from reference 11.

Citation: Dannenberg, Jr. A. 2006. Cytokine Production in Primary BCG Lesions, p 301-311. In Pathogenesis of Human Pulmonary Tuberculosis. ASM Press, Washington, DC. doi: 10.1128/9781555815684.ch19
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Image of FIGURE 2
FIGURE 2

A 16-day dermal BCG lesion in situ hybridized for IL-8 mRNA. Liquefied caseum is in the left lower part of the photograph. Solid caseum is shown at the far right of the photograph. Large macrophages in the liquefied caseum adjacent to the solid caseum are heavily labeled for IL-8 mRNA. IL-8 is a major chemokine that attracts PMN, and numerous PMN are present throughout the liquefied material. Fixed-frozen tissue section hybridized with antisense IL-8 35S-labeled RNA, autoradiographed, and counterstained with Giemsa. Magnification, ×350. Reproduced with permission from reference 11.

Citation: Dannenberg, Jr. A. 2006. Cytokine Production in Primary BCG Lesions, p 301-311. In Pathogenesis of Human Pulmonary Tuberculosis. ASM Press, Washington, DC. doi: 10.1128/9781555815684.ch19
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Image of FIGURE 3
FIGURE 3

(A) An unfixed-frozen tissue section of a 3-day dermal BCG lesion stained immunohistochemically for MCP-1 protein. Large mononuclear cells in the partly necrotic exudate between the remaining collagen fibers are darkly stained for MCP-1 protein. Anti-rabbit MCP-1 polyclonal antibody, biotinylated anti-guinea pig IgG, and the avidin-biotin-peroxidase procedure, counterstained with Giemsa. Magnification, ×200. Reproduced with permission from reference 11. (B) A lightly fixed tissue section of a 3-day dermal BCG lesion embedded in glycol methacrylate and stained with Giemsa. This photograph shows some of the histologic detail that is absent in frozen sections. In the center and to the left are a few large mononuclear cells that are similar to those stained histochemically in panel A. Note the frequent occurrence of PMN in the 3-day BCG lesions. Magnification, ×460. Reproduced with permission from reference 11.

Citation: Dannenberg, Jr. A. 2006. Cytokine Production in Primary BCG Lesions, p 301-311. In Pathogenesis of Human Pulmonary Tuberculosis. ASM Press, Washington, DC. doi: 10.1128/9781555815684.ch19
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Image of FIGURE 4
FIGURE 4

Changes in IFN-γ mRNA in rabbit BCG lesions, relative to those of GAPDH mRNA (see text). (The amount of GAPDH mRNA in cells is known to remain rather constant without wide fluctuations, as the cells up- and downregulate their various activities.) Note that the biphasic response was somewhat delayed when compared with that of the other cytokine mRNAs shown in Fig. 1. This delay suggests that the initial mononuclear cells produced cytokines (including chemokines) that subsequently upregulated the IFN-γ production in other cells (mostly in nearby lymphocytes). ***P < 0.01 for day 5 vs. day 7. The means and their standard errors are shown. Reproduced with permission from reference 11.

Citation: Dannenberg, Jr. A. 2006. Cytokine Production in Primary BCG Lesions, p 301-311. In Pathogenesis of Human Pulmonary Tuberculosis. ASM Press, Washington, DC. doi: 10.1128/9781555815684.ch19
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Image of FIGURE 5
FIGURE 5

Summary of the histologic characteristics and cytokines in early and peak rabbit dermal BCG lesions. Note that the cytokines upregulated in the early lesions were downregulated by the time the lesions peaked at 14 to 23 days. Reproduced with permission from reference 11.

Citation: Dannenberg, Jr. A. 2006. Cytokine Production in Primary BCG Lesions, p 301-311. In Pathogenesis of Human Pulmonary Tuberculosis. ASM Press, Washington, DC. doi: 10.1128/9781555815684.ch19
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Tables

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TABLE 1

Percentage of mononuclear cells stained for MCP-1 and TNF-α a

Citation: Dannenberg, Jr. A. 2006. Cytokine Production in Primary BCG Lesions, p 301-311. In Pathogenesis of Human Pulmonary Tuberculosis. ASM Press, Washington, DC. doi: 10.1128/9781555815684.ch19

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