Tuberculosis Mycobacterium tuberculosis Is Primarily Controlled by CD4 T Cells

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Tuberculosis is the leading cause of death in the world from a single infectious agent, killing about 3 million individuals every year and accounting for 18.5% of all deaths in adults between the ages of 15 and 59. About 1.79 billion people, roughly one-third of the world's population, are infected with the causative agent M. tuberculosis and are at risk of developing the disease. Long thought to have been eliminated as a 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 section of this chapter). In 2000, approximately 17,000 individuals were diagnosed with tuberculosis in the United States.

Although several Mycobacterium species can cause tuberculosis, M. tuberculosis is the principal causative agent. This organism is spread easily, and pulmonary infection usually results from inhalation of small droplets of respiratory secretions 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 response involving CD4+ T cells, which is required for immunity to tuberculosis, may be responsible for much of the tissue 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 infiltration 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 (cheeselike) 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-7 in the immune response to mycobacteria has been demonstrated with knockout mice lacking IFN-7. 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 surprising, 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.

Macrophage with bacilli

Caseous center

Bacilli

Activated macrophages

Granuloma Formation

FIGURE 17-10

A tubercle formed in pulmonary tuberculosis. [Modified from A. M. Dannenberg, 1993, Hosp. Prac. (Jan. 15):51.]

Th1 cell

Activated macrophages

Macrophage with bacilli

Caseous center

Bacilli

Activated macrophages

FIGURE 17-10

A tubercle formed in pulmonary tuberculosis. [Modified from A. M. Dannenberg, 1993, Hosp. Prac. (Jan. 15):51.]

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. tuberculosis follow a different clinical pattern: the disease progresses to chronic pulmonary tuberculosis or extrapulmonary tuberculosis. This progression may occur years after the primary infection. In this clinical pattern, accumulation of large concentrations of mycobacterial antigens within tubercles leads to extensive and continual chronic CD4+ T-cell activation 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 tubercle 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 combination, 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 after treatment begins. To avoid the side effects associated with the usual antibiotic therapy, many patients, once they feel better, stop taking the medications long before the recommended treatment period is completed. Because briefer treatment may not eradicate organisms that are somewhat resistant to the antibiotics, a multidrug-resistant strain can emerge. Noncompliance with required treatment regimes, one of the most troubling aspects of the large number of current tuberculosis cases, clearly compromises efforts to contain the spread of the disease.

Presently, the only vaccine for M. tuberculosis is an attenuated strain of M. boviscalled BCG (Bacillus Calmette-Guerin). The vaccine appears to provide fairly effective protection against extrapulmonary tuberculosis but has been inconsistent against pulmonary tuberculosis. In different studies, BCG has provided protection in anywhere from 0% to 80% of vaccinated individuals; in some cases, BCG vaccination has even increased the risk of infection. Moreover, after BCG vaccination, the tuberculin skin test cannot be used as an effective monitor of exposure to M. tuberculosis. Because of the variable effectiveness of the BCG vaccine and the inability to monitor for exposure with the skin test after vaccination, this vaccine is not used in the United States. However, the alarming increase in multidrug-resistant strains has stimulated renewed efforts to develop a more effective tuberculosis vaccine.

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