IMMUNOLOGY - Roitt I. - Mir 2000

Chapter 26. Hypersensitivity - Type IV

CELLULAR REACTIONS IN TYPE IV HYPERSENSITIVITY

Gene knockout experiments in mice have confirmed that delayed-type hypersensitivity reactions against intracellular bacterial infections require T Cells bearing αβ rather than γδ TCRs. Sensitized αβ T cells, stimulated by the relevant antigen and APCs, undergo blast transformation prior to division (Fig. 26.14). This forms The basis of the lymphocyte stimulation test (see Ch. 29). Lymphocyte stimulation is accompanied by DNA Synthesis, which can be detected by the incorporation of radiolabeled thymidine (a nucleotide essential for DNA synthesis). The test involves culturing a patient's lymphocytes with a suspected antigen to determine whether it induces Cell transformation. However, a positive result in this test merely indicates the presence of immunological memory T cells and does not necessarily reflect protective Immunity.

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Fig. 26.14. Transformed lymphocytes. Antigen-activated T cells undergo blast transformation before dividing. The micrograph shows blast cells with enlarged nuclei (one of the lymphocytes is in metaphase).

Following APC-mediated activation, T cells secrete numerous pro-caspase and pro-inflammatory cytokines that recruit and activate macrophages. These cytokines include IFNγ, lymphotoxin, IL-3, and GM-CSF. The predominance of Th1-derived cytokines is linked to T-cell activation by IL-12, a cytokine released by macrophages in response to bacterial products; this cytokine suppresses cytokine production by Th2 cells. The Role of individual cytokines can be analyzed using knockout mice lacking a specific cytokine gene. For instance, mice lacking the IFNγ gene are unable to activate macrophages and combat tuberculosis infection (Fig. 26.15). In granulomatous reactions, activated macrophages serve as the primary source of TNF, and the granuloma develops through auto-Amplification, transforming macrophages into epithelioid cells (Figs. 26.16 and 26.17). The latter continue to secrete TNF, stimulating the further formation of epithelioid cells, which fuse to form giant cells (Fig. 26.18).

Fig. 26.15. Mice lacking the IFNγ gene fail to mount macrophage activation during intracellular bacterial infection. Although macrophages accumulate at the infection site, they do not form typical granulomas. Uncontrolled infection (left graph) causes extensive tissue necrosis and animal death (right graph).

Fig. 26.16. Bacterial products stimulate macrophage secretion of IL-12. T-cell activation by this cytokine leads to the release of IFNγ and other cytokines—TNFβ, IL-3, and GM-CSF—which activate macrophages to aid in the destruction of intracellular parasites. The failure to clear the antigenic stimulus results in continuous cytokine release and the differentiation of macrophages into epithelioid cells, which secrete large amounts of TNFα. Some epithelioid cells fuse to form multinucleated giant cells.

Fig. 26.17. TNF is essential for The formation of epithelioid cell granulomas. When BCG-primed mice are administered anti-TNFα Antibodies, granulomas fail to develop.

Fig. 26.18. Epithelioid cells in a pulmonary granuloma from a patient with sarcoidosis. 1. Epithelioid and giant cells in the center stained with RFD-9 specific antibodies. 2. Mature tissue macrophages surrounding the granuloma, stained with RFD-7 specific antibodies. (Micrographs kindly provided by C. S. Munro.)