Fig. 13.33 Sequence of events in the natural history of primary pulmonary tuberculosis. This sequence commences with inhalation of virulent strains of Mycobacterium and culminates in the development of immunity and delayed hypersensitivity to the organism. (A) Events occurring in the first 3 weeks after exposure. (B) Events thereafter. The development of resistance to the organism is accompanied by conversion to a positive result on tuberculin skin testing. Cells and bacteria are not drawn to scale. IFN-γ, Interferon γ; iNOS, inducible nitric oxide synthase; MHC, major histocompatibility complex; MTb, Mycobacterium tuberculosis; TNF, tumor necrosis factor.
immunity and damaging hypersensitivity are the same, the appearance of tissue hypersensitivity also signals the acquisition of immunity to the organism. The sequence of events from inhalation of the infectious inoculum to containment of the primary focus is illustrated in
Fig. 13.33 and can be outlined as follows:
Entry into macrophages. A virulent strain of mycobacteria gains entry to macrophage endosomes, a process mediated by several macrophage receptors, including the macrophage mannose receptor and complement receptors that recognize several components of the mycobacterial cell walls.
Replication in macrophages. Once internalized, the organisms inhibit normal microbicidal responses by preventing the fusion of the lysosomes with the phagocytic vacuole, allowing the mycobacterium to persist and proliferate. Thus, the earliest phase of primary tuberculosis (the first 3 weeks) in the nonsensitized patient is characterized by bacillary proliferation within the pulmonary alveolar macrophages and air spaces, eventually resulting in bacteremia and seeding of the organisms to multiple sites. Despite the bacteremia, most individuals at this stage are asymptomatic or have a mild flulike illness.
Development of cell-mediated immunity. This occurs approximately 3 weeks after exposure. Processed mycobacterial antigens reach the draining lymph nodes and are presented to CD4 T cells by dendritic cells and macrophages. Under the influence of macrophage-secreted IL-12, CD4+ T cells of the TH1 subset are generated that are capable of secreting IFN-γ.
T cell–mediated macrophage activation and killing of bacteria. IFN-γ released by the CD4+ T cells of the TH1 subset is crucial in activating macrophages. Activated macrophages, in turn, release a variety of mediators and upregulate expression of genes with important downstream effects, including: (1) TNF, which is responsible for recruitment of monocytes, which in turn undergo activation and differentiation into the “epithelioid histiocytes” that characterize the granulomatous response; (2) inducible nitric oxide synthase (iNOS), which raises nitric oxide (NO) levels, helping to create reactive nitrogen intermediates that appear to be particularly important in killing of mycobacteria; and (3) anti-microbial peptides (defensins) that are also toxic to mycobacterial organisms.