Adaptive Immunity to Intracellular Bacteria

The major protective immune response against intracellular bacteria is T cell-mediated immunity. Individuals with deficient cell-mediated immunity, such as patients with acquired immunodeficiency syndrome (AIDS), are extremely susceptible to infections with intracellular bacteria (and viruses). The mechanisms of cell-mediated immunity were studied in the 1950s in mice, in examining protection against the intracellular bacterium L. monocytogenes. This form of immunity could be adoptively transferred to naive animals with lymphoid cells but not with serum from infected or immunized animals (see Chapter 10, Fig. 10-6).

As we discussed in Chapter 10, cell-mediated immunity consists of two types of reactions: CD4+ T cells recruit phagocytes and activate them through the actions of CD40 ligand and IFN-y, resulting in killing of phagocy-tosed microbes, and CD8+ cytotoxic T lymphocytes (CTLs) kill infected cells. Both CD4+ T cells and CD8+ T cells respond to protein antigens of phagocytosed microbes, which are displayed as peptides associated with class II and class I major histocompatibility complex (MHC) molecules, respectively. CD4+ T cells differentiate into Th1 effectors under the influence of IL-12, which is produced by macrophages and dendritic cells. The T cells express CD40 ligand and secrete IFN-y, and these two stimuli activate macrophages to produce several microbi-cidal substances, including reactive oxygen species, nitric oxide, and lysosomal enzymes. IFN-y also stimulates the

Citocinas Receptores Foto

FIGURE 15-3 Innate and adaptive immunity to intracellular bacteria. The innate immune response to intracellular bacteria consists of phagocytes and NK cells, interactions among which are mediated by cytokines (IL-12 and IFN-y). The typical adaptive immune response to these microbes is cell-mediated immunity, in which T cells activate phagocytes to eliminate the microbes. Innate immunity may control bacterial growth, but elimination of the bacteria requires adaptive immunity. These principles are based largely on analysis of Listeria monocytogenes infection in mice; the numbers of viable bacteria shown on the y-axis are relative values of bacterial colonies that can be grown from the tissues of infected mice. (Data from Unanue ER. Studies in listeriosis show the strong symbiosis between the innate cellular system and the T-cell response. Immunological Reviews 158: 11-25, 1997.)

FIGURE 15-3 Innate and adaptive immunity to intracellular bacteria. The innate immune response to intracellular bacteria consists of phagocytes and NK cells, interactions among which are mediated by cytokines (IL-12 and IFN-y). The typical adaptive immune response to these microbes is cell-mediated immunity, in which T cells activate phagocytes to eliminate the microbes. Innate immunity may control bacterial growth, but elimination of the bacteria requires adaptive immunity. These principles are based largely on analysis of Listeria monocytogenes infection in mice; the numbers of viable bacteria shown on the y-axis are relative values of bacterial colonies that can be grown from the tissues of infected mice. (Data from Unanue ER. Studies in listeriosis show the strong symbiosis between the innate cellular system and the T-cell response. Immunological Reviews 158: 11-25, 1997.)

production of antibody isotypes (e.g., IgG2a in mice) that activate complement and opsonize bacteria for phagocytosis, thus aiding the effector functions of macrophages. The stimuli for the production of these antibodies in humans are not as well defined. The importance of IL-12 and IFN-y in immunity to intracellular bacteria has been demonstrated in experimental models and in congenital immunodeficiencies. For instance, individuals with inherited mutations in receptors for IFN-y or IL-12 are highly susceptible to infections with atypical mycobacteria.

Phagocytosed bacteria stimulate CD8+ T cell responses if bacterial antigens are transported from phagosomes into the cytosol or if the bacteria escape from phagosomes and enter the cytoplasm of infected cells. In the cytoplasm, the microbes are no longer susceptible to the microbicidal mechanisms of phagocytes, and for eradication of the infection, the infected cells have to be killed by CTLs. Thus, the effectors of cell-mediated immunity, namely, CD4+ T cells that activate macrophages and CD8+ CTLs, function cooperatively in defense against intracellular bacteria (Fig. 15-4).

The macrophage activation that occurs in response to intracellular microbes is capable of causing tissue injury. This injury may be the result of delayed-type hypersensitivity (DTH) reactions to microbial protein antigens (see Chapter 18). Because intracellular bacteria have evolved to resist killing within phagocytes, they often persist for long periods and cause chronic antigenic stimulation and T cell and macrophage activation, which may result in the formation of granulomas surrounding the microbes (see Chapter 18, Fig. 18-8). The histologic hallmark of infection with some intracellular bacteria is granuloma-tous inflammation. This type of inflammatory reaction may serve to localize and prevent spread of the microbes, but it is also associated with severe functional impairment caused by tissue necrosis and fibrosis.

Tuberculosis is an example of an infection with an intracellular bacterium in which protective immunity and pathologic hypersensitivity coexist, and the host response contributes significantly to the pathology. In a primary infection with M. tuberculosis, bacilli multiply slowly in the lungs and cause only mild inflammation. The infection is contained by alveolar macrophages (and probably dendritic cells). More than 90% of infected patients remain asymptomatic, but bacteria survive in the lungs, mainly in macrophages. By 6 to 8 weeks after infection, the macrophages have traveled to the draining lymph nodes, and CD4+ T cells are activated; CD8+ T cells may also be activated later. These T cells produce IFN-y, which activates macrophages and enhances their ability to kill phagocy-tosed bacilli. TNF produced by T cells and macrophages also plays a role in local inflammation and macrophage activation. The T cell reaction is adequate to control bacterial spread. However, M. tuberculosis is capable of surviving within macrophages because components of its cell wall inhibit the fusion of phagocytic vacuoles with lysosomes. Continuing T cell activation leads to the formation of granulomas, which attempt to wall off the bacteria and are often associated with central necrosis, called caseous necrosis, which is caused by macrophage products such as lysosomal enzymes and reactive oxygen species. Necrotiz-ing granulomas and the fibrosis (scarring) that accompanies granulomatous inflammation are the principal causes of tissue injury and clinical disease in tuberculosis. Previously infected persons show cutaneous DTH reactions to skin challenge with a bacterial antigen preparation (purified protein derivative, or PPD). Bacilli may survive for

^Phagocytosed bacteria in vesicles and cytoplasm

CD4+ T cell

^Phagocytosed bacteria in vesicles and cytoplasm

CD4+ T cell

Intracellular Bacteria

FIGURE 15-4 Cooperation of CD4+ and CD8+ T cells in defense against intracellular microbes. Intracellular bacteria such as L. monocytogenes are phagocytosed by macrophages and may survive in phagosomes and escape into the cytoplasm. CD4+ T cells respond to class II MHC-associated peptide antigens derived from the intravesicular bacteria. These T cells produce IFN-y, which activates macrophages to destroy the microbes in phagosomes. CD8+ T cells respond to class I-associated peptides derived from cytosolic antigens and kill the infected cells.

FIGURE 15-4 Cooperation of CD4+ and CD8+ T cells in defense against intracellular microbes. Intracellular bacteria such as L. monocytogenes are phagocytosed by macrophages and may survive in phagosomes and escape into the cytoplasm. CD4+ T cells respond to class II MHC-associated peptide antigens derived from the intravesicular bacteria. These T cells produce IFN-y, which activates macrophages to destroy the microbes in phagosomes. CD8+ T cells respond to class I-associated peptides derived from cytosolic antigens and kill the infected cells.

many years and are contained without any pathologic consequences but may be reactivated at any time, especially if the immune response becomes unable to control the infection.

Differences among individuals in the patterns of T cell responses to intracellular microbes are important determinants of disease progression and clinical outcome (Fig. 15-5). An example of this relationship between the type of T cell response and disease outcome is leprosy, which is caused by Mycobacterium leprae. There are two polar forms of leprosy, the lepromatous and tuberculoid forms, although many patients fall into less clear intermediate groups. In lepromatous leprosy, patients have high specific antibody titers but weak cell-mediated responses to M. leprae antigens. Mycobacteria proliferate within macrophages and are detectable in large numbers. The bacterial growth and persistent but inadequate macrophage activation result in destructive lesions in the skin and underlying tissue. In contrast, patients with tuberculoid leprosy have strong cell-mediated immunity but low antibody levels. This pattern of immunity is reflected in granulomas that form around nerves and produce peripheral sensory nerve defects and secondary traumatic skin lesions but less with tissue destruction and a paucity of bacteria in the lesions. One possible reason for the differences in these two forms of disease caused by the same organism may be that there are different patterns of T cell differentiation and cytokine production in individuals. Some studies indicate that patients with the tuberculoid form of the disease produce IFN-y and IL-2 in lesions (indicative of TH1 cell activation), whereas patients with lepromatous leprosy produce less IFN-y and perhaps more IL-4 and IL-10 (suggestive of TH2 cells). In lepromatous leprosy, both the deficiency of IFN-y and the macrophage-suppressive effects of IL-10 and possibly IL-4 may result in weak cell-mediated immunity and failure to control bacterial spread. The role of TH1- and TH2-derived cytokines in determining

Th1 cell

FIGURE 15-5 Role of T cells and cytokines in determining the outcome of infections. Naive CD4+ T lymphocytes may differentiate into TH1 cells, which activate phagocytes to kill ingested microbes, and TH2 cells, which inhibit this classical pathway of macrophage activation. The balance between these two T cell subsets may influence the outcome of infections, as illustrated by Leish-mania infection in mice and mycobacterium leprae in humans.

Naive CD4+ T cell

Th1 cell

Naive CD4+ T cell

FIGURE 15-5 Role of T cells and cytokines in determining the outcome of infections. Naive CD4+ T lymphocytes may differentiate into TH1 cells, which activate phagocytes to kill ingested microbes, and TH2 cells, which inhibit this classical pathway of macrophage activation. The balance between these two T cell subsets may influence the outcome of infections, as illustrated by Leish-mania infection in mice and mycobacterium leprae in humans.

Th2 cell

Infection

Response Outcome

Leishmania major

Most mouse strains: TH1 =

Recovery

BALB/c mice: TH2 =

Disseminated infection

Mycobacterium leprae

Some patients: TH1 =

Some patients: Defective = Th1 or dominant TH2

^Tuberculoid leprosy

Lepromatous leprosy (high bacterial count)

the outcome of infection has been most clearly demonstrated in infection by the protozoan parasite Leishmania major in different strains of inbred mice (discussed later in this chapter).

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