There Are Several Phases of the DTH Response

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The development of the DTH response begins with an initial sensitization phase of 1-2 weeks after primary contact with an antigen. During this period, TH cells are activated and clonally expanded by antigen presented together with the requisite class II MHC molecule on an appropriate antigen-presenting cell (Figure 16-17a). A variety of antigen-presenting cells have been shown to be involved in the activation of a DTH response, including Langerhans cells and macrophages. Langerhans cells are dendritic cells found in the epidermis. These cells are thought to pick up antigen that enters through the skin and transport it to regional lymph nodes, where

Intracellular bacteria Mycobacterium tuberculosis Mycobacterium leprae Listeria monocytogenes Brucella abortus Intracellular fungi Pneumocystis carinii Candida albicans Histoplasma capsulatum Cryptococcus neoformans Intracellular parasites Leishmania sp.

T cells are activated by the antigen. In some species, including humans, the vascular endothelial cells express class II MHC molecules and also function as antigen-presenting cells in the development of the DTH response. Generally, the T cells activated during the sensitization phase are CD4+, primarily of the Th1 subtype, but in a few cases CD8+ cells have also been shown to induce a DTH response. The activated T cells previously were called TDTH cells to denote their function in the DTH response, although in reality they are simply a subset of activated TH1 cells (or, in some cases, TC cells).

A subsequent exposure to the antigen induces the effector phase of the DTH response (see Figure 16-17b). In the effector phase, TH1 cells secrete a variety of cytokines that recruit and activate macrophages and other nonspecific inflammatory cells. A DTH response normally does not become apparent until an average of 24 h after the second contact with the antigen; the response generally peaks 48-72 h after second contact. The delayed onset of this response reflects the time required for the cytokines to induce localized influxes of macrophages and their activation. Once a DTH response begins, a complex interplay of nonspecific cells and mediators is set in motion that can result in tremendous amplification. By the time the DTH response is fully developed, only about 5% of the participating cells are antigen-specific TH1 cells; the remainder are macrophages and other nonspecific cells.

Macrophages are the principal effector cells of the DTH response. Cytokines elaborated by TH1 cells induce blood monocytes to adhere to vascular endothelial cells and migrate from the blood into the surrounding tissues. During this process the monocytes differentiate into activated macrophages. As Chapter 2 described, activated macrophages exhibit increased levels of phagocytosis and an increased ability to kill microorganisms through various cytotoxic mediators. In addition, activated macrophages express increased levels of class II MHC molecules and cell-adhesion molecules and therefore function more effectively as antigen-presenting cells.

The influx and activation of macrophages in the DTH response is important in host defense against parasites and bacteria that live within cells, where circulating antibodies cannot reach them. The heightened phagocytic activity and the buildup of lytic enzymes from macrophages in the area of infection lead to nonspecific destruction of cells, and thus of the intracellular pathogen. Generally, the pathogen is cleared rapidly with little tissue damage. However, in some cases, especially if the antigen is not easily cleared, a prolonged DTH response can itself become destructive to the host as the intense inflammatory response develops into a visible granu-lomatous reaction. A granuloma develops when continuous activation of macrophages induces the macrophages to adhere closely to one another, assuming an epithelioid shape and sometimes fusing to form multinucleated giant cells (Figure 16-18). These giant cells displace the normal tissue cells, forming palpable nodules, and release high concentrations of lytic enzymes, which destroy surrounding tissue. In these cases, the response can damage blood vessels and lead

Intracellular pathogens and contact antigens that induce delayed-type (type IV) hypersensitivity

Intracellular bacteria Mycobacterium tuberculosis Mycobacterium leprae Listeria monocytogenes Brucella abortus Intracellular fungi Pneumocystis carinii Candida albicans Histoplasma capsulatum Cryptococcus neoformans Intracellular parasites Leishmania sp.

Intracellular pathogens and contact antigens that induce delayed-type (type IV) hypersensitivity

Intracellular viruses Herpes simplex virus Variola (smallpox) Measles virus

Contact antigens Picrylchloride Hair dyes Nickel salts Poison ivy Poison oak

VISUALIZING CONCEPTS

(a) Sensitization phase

VISUALIZING CONCEPTS

(a) Sensitization phase

Intracellular bacteria

Intracellular bacteria

Macrophage Receptor Cryptococcus

(b) Effector phase

Class II MHC

TNF receptor

(b) Effector phase

Class II MHC

TNF receptor

Sensitized

Membrane TNF-ß

Resting macrophage

Activated macrophage

Sensitized

Membrane TNF-ß

Resting macrophage

Th1 secretions:

IL-3, GM-CSF Chemokines: IL-8, MCAF, MIF

Activated macrophage

Effects of macrophage activation: T Class II MHC

molecules T TNF receptors T Oxygen radicals T Nitric oxide

FIGURE 16-17

Overview of the DTH response. (a) In the sensiti-zation phase after initial contact with antigen (e.g., peptides derived from intracellular bacteria), TH cells proliferate and differentiate into Th1 cells. Cytokines secreted by these T cells are indicated by the dark blue balls. (b) In the effector phase after subsequent exposure of sen sitized Th1 cells to antigen, the TH1 cells secrete a variety of cytokines and chemokines. These factors attract and activate macrophages and other nonspecific inflammatory cells. Activated macrophages are more effective in presenting antigen, thus perpetuating the DTH response, and function as the primary effector cells in this reaction.

to extensive tissue necrosis. The response to Mycobacterium tuberculosis illustrates the double-edged nature of the DTH response. Immunity to this intracellular bacterium involves a DTH response in which activated macrophages wall off the organism in the lung and contain it within a granuloma-type lesion called a tubercle. Often, however, the concentrated release of lytic enzymes from the activated macrophages within tubercles damages lung tissue. Some examples of truly hypersensitive conditions, in which tissue damage far outweighs any beneficial effects, are described in Chapter 17.

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