Type IV: Delayed-type hypersensitivity—Unlike type I, II, and III hypersensitivities, delayed-type hypersensitivity (DTH) is cell-mediated, and responses occur 2–3 days after exposure to the sensitizing antigen. DTH is caused by antigen-specific DTH Th1 cells and induces a local inflammatory response that causes tissue damage characterized by the influx of antigen-non-specific inflammatory cells, especially macrophages. These cells are recruited under the influence of Th1-produced cytokines (Figure 55–6), which chemoattract circulating monocytes and neutrophils, induce myelopoiesis, and activate macrophages. The activated macrophages are primarily responsible for the tissue damage associated with DTH. Although widely considered to be deleterious, DTH responses are very effective in eliminating infections caused by intracellular pathogens such as Mycobacterium tuberculosis and Leishmania species. Clinical manifestations of DTH include tuberculin and contact hypersensitivities. Tuberculosis exposure is determined using a DTH skin test. Positive responses show erythema and induration caused by accumulation of macrophages and DTH T (TDTH) cells at the site of the tuberculin injection. Poison ivy is the most common cause of contact hypersensitivity, in which pentadecacatechol, the lipophilic chemical in poison ivy, modifies cellular tissue and results in a DTH T-cell response.
Sensitization phase: Effector phase: initial contact secondary contact with antigen with antigen
Macrophage Antigen-presenting cell (eg, macrophage, Langerhans cell) Class II MHC TCR CD4 IL-1 IL-1 IL-2 IL-2 IL-2 Memory TDTH IL-2 receptor Allergen Proliferation and    differentiation T helper cell (TH1) TDTH
Chemotaxis of macrophages
Activation of macrophages (increased phagocytic and microbicidal activities)
Induction of myelopoiesis of macrophage and neutrophil precursors
Chemotaxis and extravasation of macrophages
FIGURE 55–6 Mechanism of type IV hypersensitivity (DTH). In the sensitization phase, the processed allergen (eg, from poison ivy) is presented to CD4 TH1 cells by antigen-presenting cells in association with class II MHC. T cells are induced to express IL-2 receptors and are stimulated to proliferate and differentiate into memory TDTH cells. Secondary contact with antigen triggers the effector phase, in which memory TDTH cells release cytokines that attract and activate nonspecific inflammatory macrophages and neutrophils. These cells display increased phagocytic and microbicidal activities and release large quantities of lytic enzymes that cause extensive tissue damage.