Chapter 24 : Immune Mechanisms of Protection

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This chapter focuses on the immune mechanisms involved in protective immunity against tuberculosis, with the awareness that in most cases the immune response activated during infection with may be remarkably powerful yet insufficient. M. Lurie and E. Suter independently found that macrophages from immune animals expressed tuberculostatic activities, whereas those from normal animals permitted unrestricted bacillary multiplication. Although these studies suggested involvement of specific immune mechanisms, the investigators did not contest alternative strategies when they realized that immune serum did not influence tuberculostasis by mononuclear phagocytes (MP). The use of oxygen radical scavengers to probe the significance of reactive oxygen intermediates (ROI) in the antimycobacterial function of macrophages can potentially generate misleading information because of nonspecific effects of peroxynitrite anion, NO, superoxide anion chemicals. More importantly, the role that RNIs play in defense against pathogens has not been established in humans. Mycobactins, a group of iron-chelating growth factors of mycobacteria, have been considered a possible virulence factor of . In tuberculosis, the port of entry as well as the major organ of disease is the lung. Due the relationship between and host immunity underlying infection is a labile one, any diminution of protective immunity will cause progression into clinical disease.

Citation: Chan J, Kaufmann S. 1994. Immune Mechanisms of Protection, p 389-415. In Bloom B (ed), Tuberculosis. ASM Press, Washington, DC. doi: 10.1128/9781555818357.ch24
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Figure 1

Antituberculous macrophage activities and evasion mechanisms. Accumulating evidence suggests that M. tuberculosis enters macrophages via specific binding to cell surface molecules of phagocytes. It has been reported that the tubercle bacillus can bind directly to the mannoase receptor via the cell wall-associated, mannosylated glycolipid LAM (1) or indirectly via complement receptors of the integrin family (CR1, CR3) or Fc receptors (2). Phagocytosis (3), triggered by engaging certain cell surface molecules such as the Fc receptor, stimulates the production of ROI via activation of the oxidative burst (4). Experimental data indicate that M. tuberculosis can interfere with the toxic effect of ROI by various mechanisms. First, various mycobacterial compounds including glycolipids (GL), sulfatides (ST), and LAM can downregulate the oxidative cytotoxic mechanism (5; see text for details). Second, uptake via CR1 bypasses activation of the respiratory burst. Cytokine-activated macrophages produce RNI that, at least in the mouse system, mediate potent antimycobacterial activity (6). The acidic condition of the phagolysosomal vacuole can be conducive to the toxic effect of RNI (7). However, NH4+ production by M. tuberculosis may attenuate the potency of the l-arginine-dependent antimycobacterial mechanism and that of lysosomal enzymes (8), which operate best at an acidic pH. In addition, mycobacterial products such as sulfatides and NH4+ may interfere with phagolysosomal fusion (9). Finally, the tubercle bacillus may evade the highly toxic environment by escaping into the cytoplasm via the production of hemolysin (10).

Citation: Chan J, Kaufmann S. 1994. Immune Mechanisms of Protection, p 389-415. In Bloom B (ed), Tuberculosis. ASM Press, Washington, DC. doi: 10.1128/9781555818357.ch24
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Figure 2

Relationship between intracellular persistence of M. tuberculosis, antigen type, and T-cell subset activation. (1) M. tuberculosis replicating in the phagosome secretes proteins that are degraded into peptides and then translocated to the cell surface by MHC class II molecules. (2) MHC class I molecules capture M. tuberculosis peptides derived from secreted proteins in the cytoplasm. Either the proteins or peptides had been translocated from the endosomal into the cytoplasmic compartment, or they were secreted into the cytoplasm by M. tuberculosis after its evasion of the phagosome. Later, M. tuberculosis is killed and degraded, thus giving rise to somatic proteins. (3) Peptides derived from M. tuberculosis killed in the phagosome contact MHC class II molecules. (4) Peptides from somatic proteins present in the cytoplasm are charged to MHC class I molecules. (5) Neither the source of peptides nor the presentation molecules involved in γ/δ T-cell stimulation are fully understood. This sequence of events leads to a first wave of T cells with specificity for secreted proteins followed by a second wave of T cells with specificity for somatic proteins. Ag, antigen.

Citation: Chan J, Kaufmann S. 1994. Immune Mechanisms of Protection, p 389-415. In Bloom B (ed), Tuberculosis. ASM Press, Washington, DC. doi: 10.1128/9781555818357.ch24
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