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Chapter 3 : Pathophysiology and Immunology
Category: Clinical Microbiology; Bacterial Pathogenesis
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This chapter talks about pathophysiology and immunology of tuberculosis. The pathogenesis of human pulmonary tuberculosis can be considered as a series of battles between the host and the tubercle bacillus. The chapter discusses the measures for reducing the incidence of new cases of clinical tuberculosis, and gives an overview of five stages of pulmonary tuberculosis. It reviews the innate and acquired (adaptive) immune factors that play a role in tuberculosis. The term tissue-damaging delayed-type hypersensitivity (DTH) is used for the immunological reaction that causes necrosis. The chapter explores the major types of lymphocytes. Additional insight has recently been gained into the adjuvanticity of tuberculosis vaccines. In dermal BCG lesions, the percentage of mononuclear cells containing cytokine mRNA and protein was highest during the first 3 days. This finding suggests that the most effective tuberculosis vaccines would contain not only the most appropriate mycobacterial antigens but also mycobacterial adjuvants that recruit the largest number of macrophages, lymphocytes, and dendritic cells (DCs) into local sites of antigen deposition. Combination vaccines which consist of BCG and one or more booster immunizations with important mycobacterial antigens (including those produced by DNA vaccines) will probably provide the most effective protection against active disease. The major research advances in immunology that have direct bearing on the pathogenesis of tuberculosis are also described in the chapter. They include interactions between innate immunity and acquired immunity, interactions among the cytokines, and upregulating and downregulating mechanisms of both inflammatory and immune response.
Stages in pulmonary tuberculosis. (A) Stage 1: an AM that has ingested and is destroying the two tubercle bacilli in the phagocytic vacuole. The cytoplasm of this macrophage is darkly shaded to depict the high degree of AM activation, i.e., high levels of lysosomal and oxidative enzymes ( 72 ). (B) Stage 2: an early primary tubercle, in which tubercle bacilli have multiplied logarithmically within macrophages that have emigrated from the bloodstream into the developing lesion. These newly arriving phagocytes are nonactivated, so the cytoplasm of these macrophages is unshaded to depict the lack of activation. In fact, virulent tubercle bacilli grow well within the phagocytic vacuoles of these nonactivated macrophages. Stage 2 is called the stage of symbiosis ( 64 , 65 , 146 ) since the bacilli are multiplying, the macrophages are accumulating, and neither is destroyed. (C) Stage 3: a tubercle 3 weeks of age with a caseous necrotic center and a peripheral accumulation of partly activated macrophages (lightly shaded) and lymphocytes (small dark cells). The first stages of caseation occur when the tissue-damaging DTH response (to the tuberculin-like products of the bacilli) kills the nonactivated macrophages that have allowed the bacilli to grow logarithmically within them. The dead and dying macrophages are depicted as fragmented cell membranes. Intact and fragmented bacilli are present, both within macrophages and within the caseum. Reprinted with permission from Tuberculosis: Pathogenesis, Protection, and Control ( 76 ) (see also pages 23 to 29 in reference 69 ).
Changes in the number of virulent human-type tubercle bacilli in the lungs of natively resistant rabbits and natively susceptible rabbits at different intervals after the quantitative airborne inhalation of these bacilli ( 150 ). By 7 days after infection, the resistant animals had inhibited the growth of the bacilli 20 to 30 times more effectively than did the susceptible animals, but from then on, the two curves were parallel. At 4 to 5 weeks, susceptible animals had about 13 times the number of primary pulmonary tubercles present in the resistant animals. Means and standard errors are shown. The number of bacilli in the lungs of the resistant group failed to decrease during the period illustrated, because liquefaction with extracellular multiplication of the bacilli readily occurred in the resistant rabbits but only rarely occurred in the susceptible rabbits ( 146 , 150 ). The macrophages of the resistant rabbits apparently developed higher levels of hydrolytic enzymes ( 70 ). Reprinted with permission from American Review of Tuberculosis and Pulmonary Diseases ( 150 ) (see also page 23 in reference 69 ).
(A) Stage 4a: an established tubercle 4 to 5 weeks of age representing that found in Lurie’s susceptible rabbits. It has an enlarging caseous center. The bacilli escaping from the edge of this center are ingested by nonactivated (incompetent) macrophages. In such macrophages, the bacilli again find a favorable intracellular environment in which to multiply. They do so until again the tissue-damaging immune response kills these new bacillus-laden macrophages and the area of caseous necrosis enlarges. This sequence may be repeated many times. The living tissue is destroyed, and the bacilli spread by the lymphatic and hematogenous routes to other sites, where the tissue destruction continues. Several partly activated macrophages (lightly shaded) are included to show that these susceptible rabbits develop only weak CMI. This pattern of tuberculosis is seen in immunosuppressed individuals, including nonterminal HIV/AIDS patients. (B) Stage 4b: an established tubercle 4 or 5 weeks of age representing those found in Lurie’s resistant rabbits. The caseous center remains small because the bacilli escaping from its edge are ingested by highly activated (competent) macrophages (darkly shaded) that surround the caseum. In such activated macrophages, the bacilli cannot multiply and are eventually destroyed. Such effective macrophages are the result of activation by T cells and their cytokines. If the caseous center remains solid and does not liquefy, the disease will be arrested by this CMI process, because further tissue destruction does not occur. This scenario occurs in healthy immunocompetent human beings who show positive tuberculin reactions and yet no clinical and often no X-ray evidence of the disease. Reprinted with permission from Tuberculosis: Pathogenesis, Protection, and Control ( 76 ) (see also page 27 in reference 69 ).
Stage 5: a recently formed small cavity discharging liquefied caseous material into a bronchus. In this liquefied material, the bacilli have multiplied profusely and extracellularly. With such large numbers of bacilli, there is an increased likelihood of a mutation resulting in antimicrobial resistance. Also, the large quantities of bacilli and their antigens in the liquefied caseum are too much for even a formerly effective CMI to control, and the DTH reaction to them destroys nearby tissues, including the wall of an adjacent bronchus (illustrated here). The bacilli are then discharged into the airways, where they disseminate to other parts of the lung and to the environment. Reprinted with permission from Tuberculosis: Pathogenesis, Protection, and Control ( 76 ) (see also page 29 in reference 69 ).
A tissue section of a 10-day (rabbit) pulmonary BCG lesion. In the caseous center are disintegrated β-galactosidase-negative epithelioid cells and more than 10 faintly stained tubercle bacilli. (β-Galactosidase activity is our histochemical marker for activated macrophages that are capable of destroying tubercle bacilli [ 9 , 59 , 74 ].) Around the caseous center are viable, poorly activated β-galactosidase-negative mononuclear cells (DCs, macrophages, and lymphocytes) from the bloodstream, which control the fate of the lesion. The highly activated pulmonary AM, staining 3+ and 4+ for β-galactosidase, have accumulated in the surrounding alveolar spaces, rather far from the bacilli in the center. Although this lesion was produced by the intravenous injection of tubercle bacilli, tubercles produced by the inhalation of bacilli should show the same pattern. Specifically, bacilli are released from weakly activated pulmonary AM that failed to control the initial bacillary multiplication. These bacilli and host cytokines chemotactically attract new nonactivated macrophages (from the bloodstream), which cannot control the multiplication of tubercle bacilli in their cytoplasm (until they become activated by antigen-specific T lymphocytes). This photograph clearly demonstrates that pulmonary AM play a minor role in controlling the fate of established pulmonary tubercles, but these AM play a major role in destroying endogenous and exogenous tubercle bacilli that enter the alveolar spaces. Magnification, ×400. Reprinted with permission from American Journal of Pathology ( 219a ) (see also page 25 in reference 69 ).
Tissue section of a tuberculous lesion from one of Lurie’s genetically susceptible rabbits 2 weeks after the inhalation of virulent human-type tubercle bacilli. The nonactivated macrophages from the bloodstream contain numerous (rod-shaped) acid-fast bacilli. Two weeks is near the end of stage 2, the stage of symbiosis: the bacilli have grown logarithmically within these nonactivated macrophages with no apparent damage to the cells. Magnification, ×855. Reprinted with permission from American Review of Tuberculosis and Pulmonary Diseases ( 150 ) (see also page 25 in reference 69 ).
Tissue section of a 12-day (rabbit) dermal BCG lesion. Highly activated macrophages (stained dark blue for β-galactosidase) surround the caseous center. Therefore, bacilli released from dead and dying macrophages will now be ingested by macrophages able to inhibit intracellular bacillary growth. Magnification, ×120. Reprinted with permission from American Journal of Pathology ( 219a ) (see also page 101 in reference 69 ).
Tubercle bacilli growing profusely in the liquefied caseum in the wall of an early rabbit pulmonary cavity. Such bacillary growth occurs when the metabolism of the bacilli changes from dormancy in solid caseum to extracellular growth in liquefied caseum. For bacillary growth to occur, the composition of the liquefied caseum must be favorable. Also, oxygen (from the airways) enhances such growth ( 54 ). Similar bacillary growth has been found in many human tuberculosis cavities. Magnification, ×600. Reprinted with permission from Clinical and Diagnostic Laboratory Immunology ( 54 ) (see also page 45 in reference 69 ).
Tissue section of an area of tuberculous pneumonia in a lung of a 47-year-old man. A large proportion of the cellular exudate in the alveolar spaces has undergone caseous necrosis, and infiltrating cells thicken the alveolar septa. Magnification, ×266. From the collection of the late A. R. Rich and W. G. MacCallum, Department of Pathology, School of Medicine, The Johns Hopkins University (see also page 41 in reference 69 ).
An example of liquefaction and ulceration in the skin of a rabbit produced by the intradermal injection of BCG. In the photograph on the right, the lesion contents were exposed by cutting it with a scalpel. Reprinted with permission from Tuberculosis (Edinburgh) ( 70 ).
CMI activating macrophages in a tuberculous lesion. Mononuclear phagocytes that entered the lesion from the bloodstream are activated by the cytokines of antigen-specific T lymphocytes that had also entered the lesion. (“LK” stands for lymphokines, the former name for lymphocyte cytokines.) Antigen-specific lymphocytes produce these cytokines when stimulated by the bacillus and its products. Only activated macrophages seem capable of destroying the tubercle bacillus. Reprinted with permission from Mycobacterial Infections of Zoo Animals ( 60 ) (see also page 100 in reference 69 ).
Tissue section of a 21-day rabbit dermal BCG lesion, showing a group of activated macrophages (epithelioid cells) stained darkly for the lysosomal enzyme β-galactosidase. (As stated in the legend to Fig. 5 , β-galactosidase activity is our histochemical marker for activated macrophages that are capable of destroying tubercle bacilli [ 9 , 59 , 74 ].) Although perifocal tuberculous granulation tissue contains hundreds of macrophages, only those macrophages in locations where tubercle bacilli (and their products) are present become activated and develop the power to destroy the bacillus. In other words, the acquired cellular resistance (produced by CMI) is a local phenomenon. The darker the macrophage is stained for β-galactosidase, the more it resembles the mature epithelioid cell that Lurie identified with the destruction of the tubercle bacillus ( 9 , 146 ). Magnification, ×160. Reprinted with permission from Bacteriological Reviews ( 59 ) (see also page 103 in reference 69 ).
Macrophages stained both for β-galactosidase activity and for acid-fast bacilli in a BCG lesion of a rabbit injected intradermally 21 days previously. The macrophage near the center shows negligible β-galactosidase activity. It contains numerous bacilli and has ruptured. Another macrophage (just adjacent) shows high β-galactosidase activity. It contains no bacilli but apparently is ingesting the bacilli released from the ruptured cell. These two cells illustrate how CMI works; i.e., CMI produces locally many highly activated macrophages that can ingest (and destroy) bacilli released from ineffectual macrophages ( 9 ). Several other activated macrophages are also shown in this photograph. Magnification, ×1,600. Reprinted from reference 59 (see also page 102 in reference 69 ).