400 PART Iv The Immune System in Health and Disease public health problem in the United States, tuberculosis re- emerged in the early 1990s, particularly in the inner cities and in areas where Hiv-infection levels are high(see the last sec- tion of this chapter). In 2000, approximately 17,000 individu-THl cell als were diagnosed with tuberculosis in the United States Although several Mycobacterium species can cause tube llosis, M. tuberculosis is the principal causative agent. Th Activated nacrophages organism is spread easily, and pulmonary infection usually results from inhalation of small droplets of respiratory secre- tions containing a few bacilli. The inhaled bacilli are ingested macrophage by alveolar macrophages and are able to survive and multiply intracellularly by inhibiting formation of phagolysosomes When the infected macrophages lyse, as they eventually do, Caseous large numbers of bacilli are released. A cell-mediated re- center sponse involving CD4* T cells, which is required for immu- nity to tuberculosis, may be responsible for much of the tis- Bacilli sue damage in the disease. CD4 T-cell activity is the basis fo the tuberculin skin test to the purified protein derivative PPD)from M. tuberculosis(see Chapter 14) Activated Upon infection with M. tuberculosis, the most common macrophages clinical pattern, termed pulmonary tuberculosis, appears in about 90% of those infected. In this pattern, CD4* T cells are activated within 2-6 weeks after infection, inducing the infil- tration of large numbers of activated macrophages. These FIGURE 17-10 A tubercle for cells wall off the organism inside a granulomatous lesion Modified from A M. Dannenberg, 1993, Hosp. Prac. (Jan. 15): 51.1 called a tubercle( figure 17-10). a tubercle consists of a few mall lymphocytes and a compact collection of activated macrophages, which sometimes differentiate into epithelioid cells or multinucleated giant cells. The massive activation of nacrophages that occurs within tubercles often results in the The CD4* T-cell-mediated immune response mounted concentrated release of lytic enzymes. These enzymes destro by the majority of people exposed to M. tuberculosis thus nearby healthy cells, resulting in circular regions of necrotic controls the infection and later protects against reinfection. tissue, which eventually form a lesion with a caseous (cheese- However, about 10% of individuals infected with M. tuber like)consistency(see Figure 17-10). As these caseous lesions culosis follow a different clinical pattern: the disease pro- heal, they become calcified and are readily visible on x-rays, gresses to chronic pulmonary tuberculosis or extrapulmonary where they are called Ghon complexes tuberculosis. This progression may occur years after the Because the activated macrophages suppress proliferation mary infection. In this clinical pattern, accumulation of large of the phagocytosed bacilli, infection is contained. Cytokines concentrations of mycobacterial antigens within tubercles produced by CD4* T cells(tHI subset) play an important leads to extensive and continual chronic CD4 T-cell activa- role in the response by activating macrophages, so that they tion and ensuing macrophage activation. The resulting high are able to kill the bacilli or inhibit their growth. The role of concentrations of lytic enzymes cause the necrotic caseous IFN-y in the immune response to mycobacteria has been lesions to liquefy, creating a rich medium that allows the tuber demonstrated with knockout mice lacking IFN-y. These mice cle bacilli to proliferate extracellularly. Eventually the lesions died when they were infected with an attenuated strain of rupture, and the bacilli disseminate in the lung and/or mycobacteria(BCG), whereas IFN-y* normal mice survive. are spread through the blood and lymphatic vessels to the Recent studies have revealed high levels of IL-12 in the pleural cavity, bone, urogenital system, meninges, peritoneum, pleural effusions of tuberculosis patients. The high levels or skin. of IL-12, produced by activated macrophages, are not sur- Tuberculosis is treated with several drugs used in combina- prising, given the decisive role of IL-12 in stimulating THl- tion, including isoniazid, rifampin, streptomycin, pyrazina- mediated responses(see Figure 12-12). In mouse models of mide, and ethambutol. The combination therapy of isoniazid tuberculosis, IL-12 has been shown to increase resistance to and rifampin has been particularly effective. The intracellular the disease. Not only does IL-12 stimulate development of growth of M. tuberculosis makes it difficult for drugs to reach THl cells, but it also may contribute to resistance by inducing the bacilli. For this reason, drug therapy must be continued the production of chemokines that attract macrophages to at least 9 months to eradicate the bacteria. Some patients with the site of infection. When IL- 12 is neutralized by antibody to tuberculosis do not exhibit any clinical symptoms, and some IL-12, granuloma formation in tuberculous mice is blocked. patients with symptoms begin to feel better within 2-4 wepublic health problem in the United States, tuberculosis re￾emerged in the early 1990s, particularly in the inner cities and in areas where HIV-infection levels are high (see the last sec￾tion of this chapter). In 2000, approximately 17,000 individu￾als were diagnosed with tuberculosis in the United States. Although several Mycobacterium species can cause tuber￾culosis, M. tuberculosis is the principal causative agent. This organism is spread easily, and pulmonary infection usually results from inhalation of small droplets of respiratory secre￾tions containing a few bacilli. The inhaled bacilli are ingested by alveolar macrophages and are able to survive and multiply intracellularly by inhibiting formation of phagolysosomes. When the infected macrophages lyse, as they eventually do, large numbers of bacilli are released. A cell-mediated re￾sponse involving CD4+ T cells, which is required for immu￾nity to tuberculosis, may be responsible for much of the tis￾sue damage in the disease. CD4+ T-cell activity is the basis for the tuberculin skin test to the purified protein derivative (PPD) from M. tuberculosis (see Chapter 14). Upon infection with M. tuberculosis, the most common clinical pattern, termed pulmonary tuberculosis, appears in about 90% of those infected. In this pattern, CD4+ T cells are activated within 2–6 weeks after infection, inducing the infil￾tration of large numbers of activated macrophages. These cells wall off the organism inside a granulomatous lesion called a tubercle (Figure 17-10). A tubercle consists of a few small lymphocytes and a compact collection of activated macrophages, which sometimes differentiate into epithelioid cells or multinucleated giant cells. The massive activation of macrophages that occurs within tubercles often results in the concentrated release of lytic enzymes. These enzymes destroy nearby healthy cells, resulting in circular regions of necrotic tissue, which eventually form a lesion with a caseous (cheese￾like) consistency (see Figure 17-10). As these caseous lesions heal, they become calcified and are readily visible on x-rays, where they are called Ghon complexes. Because the activated macrophages suppress proliferation of the phagocytosed bacilli, infection is contained. Cytokines produced by CD4+ T cells (TH1 subset) play an important role in the response by activating macrophages, so that they are able to kill the bacilli or inhibit their growth. The role of IFN- in the immune response to mycobacteria has been demonstrated with knockout mice lacking IFN-. These mice died when they were infected with an attenuated strain of mycobacteria (BCG), whereas IFN-+ normal mice survive. Recent studies have revealed high levels of IL-12 in the pleural effusions of tuberculosis patients. The high levels of IL-12, produced by activated macrophages, are not sur￾prising, given the decisive role of IL-12 in stimulating TH1- mediated responses (see Figure 12-12). In mouse models of tuberculosis, IL-12 has been shown to increase resistance to the disease. Not only does IL-12 stimulate development of TH1 cells, but it also may contribute to resistance by inducing the production of chemokines that attract macrophages to the site of infection. When IL-12 is neutralized by antibody to IL-12, granuloma formation in tuberculous mice is blocked. The CD4+ T-cell–mediated immune response mounted by the majority of people exposed to M. tuberculosis thus controls the infection and later protects against reinfection. However, about 10% of individuals infected with M. tuber￾culosis follow a different clinical pattern: the disease pro￾gresses to chronic pulmonary tuberculosis or extrapulmonary tuberculosis. This progression may occur years after the pri￾mary infection. In this clinical pattern, accumulation of large concentrations of mycobacterial antigens within tubercles leads to extensive and continual chronic CD4+ T-cell activa￾tion and ensuing macrophage activation. The resulting high concentrations of lytic enzymes cause the necrotic caseous lesions to liquefy, creating a rich medium that allows the tuber￾cle bacilli to proliferate extracellularly. Eventually the lesions rupture, and the bacilli disseminate in the lung and/or are spread through the blood and lymphatic vessels to the pleural cavity, bone, urogenital system, meninges, peritoneum, or skin. Tuberculosis is treated with several drugs used in combina￾tion, including isoniazid, rifampin, streptomycin, pyrazina￾mide, and ethambutol. The combination therapy of isoniazid and rifampin has been particularly effective. The intracellular growth of M. tuberculosis makes it difficult for drugs to reach the bacilli. For this reason, drug therapy must be continued for at least 9 months to eradicate the bacteria. Some patients with tuberculosis do not exhibit any clinical symptoms, and some patients with symptoms begin to feel better within 2–4 weeks 400 PART IV The Immune System in Health and Disease TH1 cell Activated macrophages Macrophage with bacilli Activated macrophages Caseous center Bacilli FIGURE 17-10 A tubercle formed in pulmonary tuberculosis. [Modified from A. M. Dannenberg, 1993, Hosp. Prac. ( Jan. 15):51.]