FIGURE 18-6 Delayed-type hypersensitivity reaction.
Infection or immunization (vaccination) sensitizes an individual, and subsequent challenge with an antigen from the infectious agent elicits a DTH reaction. The reaction is manifested by induration with redness and swelling at the site of the challenge, which is undetectable at ~4 hours and peaks at ~48 hours. (Courtesy of Dr. J. Faix, Department of Pathology, Stanford University School of Medicine, Palo Alto, California.)
endothelial cells lining these venules become plump, show increased biosynthetic organelles, and become leaky to plasma macromolecules. Fibrinogen escapes from the blood vessels into the surrounding tissues, where it is converted into fibrin. The deposition of fibrin and, to a lesser extent, the accumulation of T cells and monocytes within the extravascular tissue space around the injection site cause the tissue to swell and become firm (indurated). Induration, a diagnostic feature of DTH, is detectable by about 18 hours after the injection of antigen and is maximal by 24 to 48 hours. In clinical practice, loss of DTH responses to universally encountered antigens (e.g., Candida antigens) is an indication of deficient T cell function, a condition known as anergy. (This general loss of immune responsiveness is different from lymphocyte anergy, a mechanism for maintaining tolerance to specific antigens, discussed in Chapter 14.)
Although DTH has traditionally been considered a TH1-mediated injurious reaction, other T cells may contribute to the inflammation. In some DTH lesions, neu-trophils are prominent, suggesting the involvement of TH17 cells. In infections by some helminthic parasites, reactions against the parasite eggs elicit DTH with a strong component of eosinophils. In these cases, a role for Th2 cytokines has been demonstrated. CD8+ T cells also produce IFN-y and may contribute to some DTH reactions, especially in the skin.
Chronic DTH reactions can develop if a TH1 response to an infection activates macrophages but fails to eliminate phagocytosed microbes. If the microbes are localized in a small area, the reaction produces nodules of inflammatory tissue called granulomas (Fig. 18-8A). Chronic DTH, as exemplified by granulomatous inflammation, is caused by prolonged cytokine signals (Fig. 18-8B). In such reactions, the activated T cells and macrophages continue to produce cytokines and growth factors, which amplify the reactions of both cell types and progressively modify the local tissue environment. The result is a cycle of tissue injury and chronic inflammation followed by replacement with connective tissue (fibrosis). In chronic DTH reactions, activated macrophages also undergo changes in response to persistent cytokine signals. These macrophages develop increased cytoplasm and cytoplas-mic organelles and histologically may resemble skin epithelial cells, because of which they are sometimes called epithelioid cells. Activated macrophages may fuse to form multinucleate giant cells. Granulomatous inflammation is an attempt to contain the infection but is also the cause of significant tissue injury and functional impairment. This type of inflammation is a characteristic response to some persistent microbes, such as M. tuberculosis and some fungi, and represents a form of chronic DTH with fibrosis. Much of the respiratory difficulty associated with tuberculosis or chronic fungal infection of the lung is caused by replacement of normal lung with fibrotic tissue and not directly attributable to the microbes.
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