Numerous Cytokines Participate in the DTH Reaction

Among the cytokines produced by TH1 cells are a number that attract and activate macrophages to the site of infection. IL-3 and GM-CSF induce localized hematopoiesis of the granulocyte-monocyte lineage. IFN-7 and TNF-ß (together with macrophage-derived TNF-a and IL-1) act on nearby endothelial cells, inducing a number of changes that facilitate extravasation of monocytes and other nonspecific inflam-

Th1 cell

Th1 cell

Intracellular Bacteria

Multinucleated giant cell

Epithelioid cell

Intracellular bacteria

FIGURE 16-18

Activated macrophage

Multinucleated giant cell

Epithelioid cell

Intracellular bacteria

FIGURE 16-18

Activated macrophage

A prolonged DTH response can lead to formation of a granuloma, a nodule-like mass. Lytic enzymes released from activated macrophages in a granuloma can cause extensive tissue damage.

matory cells. Circulating neutrophils and monocytes adhere to the adhesion molecules displayed on the vascular endothelial cells and extravasate into the tissue spaces. Neutrophils appear early in the reaction, peaking by about 6 h and then declining in numbers. The monocyte infiltration occurs between 24 and 48 h after antigen exposure.

As the monocytes enter the tissues to become macrophages, they are chemotactically drawn to the site of the DTH response by chemokines such as monocyte chemotac-tic and activating factor (MCAF). Another chemokine called migration-inhibition factor (MIF) inhibits macrophages from migrating beyond the site of a DTH reaction. As macrophages accumulate at the site of a DTH reaction, they are activated by cytokines, particularly IFN-7 and membrane-bound TNF-p produced by TH1 cells. As noted earlier, macrophages become more effective as antigen-presenting cells upon activation. Thus, the activated macrophages can efficiently mediate activation of more T cells, which in turn secrete more cytokines that recruit and activate even more macrophages. This self-perpetuating response, however, is a double-edged sword, with a fine line existing between a beneficial, protective response and a detrimental response characterized by extensive tissue damage.

A report of experiments with knockout mice that could not produce IFN-7 demonstrated the importance of this cytokine in the DTH response. When these knockout mice were infected with an attenuated strain of Mycobacterium bovis known as BCG (Bacille Calmette Guerin), nearly all the animals died within 60 days, whereas wild-type mice survived (Figure 16-19). Macrophages from the IFN-7 knockout mice were shown to have reduced levels of class II MHC molecules and of bactericidal metabolites such as nitric oxide and superoxide anion.

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