Type IV (delayed-type/cell-mediated) hypersensitivity is unique among the hypersensitivity reactions in being antibody-independent, mediated instead by sensitized T lymphocytes, and characteristically taking 24–72 hours to develop after antigen re-exposure (hence “delayed”).
Mechanism: on first exposure, antigen is processed and presented by antigen-presenting cells, generating sensitized memory CD4+ Th1 cells. On re-exposure to the same antigen, these sensitized Th1 cells recognize antigen presented on MHC class II, become activated, and secrete cytokines — notably IFN-γ, which activates macrophages, enhancing their phagocytic/microbicidal capacity, and recruits further macrophages and lymphocytes, producing a mononuclear cell (lymphocyte/macrophage)-rich inflammatory infiltrate. A related subtype involves direct CD8+ cytotoxic T lymphocyte-mediated killing of target cells presenting the antigen on MHC class I.
Clinical examples:
Tuberculin (Mantoux) reaction — the prototype, used diagnostically to detect prior sensitization to M. tuberculosis antigens.
Granulomatous hypersensitivity — a chronic form seen when the antigen (e.g., persistent intracellular M. tuberculosis, M. leprae) cannot be cleared, leading to granuloma formation with caseation necrosis, epithelioid cells, and Langhans giant cells.
Contact dermatitis — to nickel, poison ivy (urushiol), certain cosmetics/chemicals, where the chemical acts as a hapten, binding to skin proteins to form a complete antigen.
Graft rejection (acute cellular rejection) and certain drug reactions.
Laboratory demonstration: the tuberculin skin test (Mantoux) and patch testing (for contact allergens) are the classical in-vivo tests; interferon-gamma release assays (IGRAs) provide an in-vitro correlate for tuberculosis sensitization.
