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Type III hypersensitivity involves immune complex deposition in tissues, occurring when antigen-antibody ratios favor soluble complex formation. Complexes deposit in blood vessels, joints, and kidneys where complement activation attracts neutrophils causing vasculitis and tissue damage. Type IV hypersensitivity is delayed cell-mediated immunity where antigen-specific CD4+ and CD8+ T cells infiltrate tissues 24-72 hours after exposure (contact dermatitis, TB skin test). Unlike immediate hypersensitivities, both involve activation of cellular immunity and produce delayed reactions.
Diagram immune complex formation and deposition in vasculature, joint, and kidney. Compare Type III and Type IV kinetics and cellular participants (antibodies vs T cells).
You already understand that antibodies bind antigens and that CD4+ T helper cells coordinate adaptive immune responses. Types III and IV hypersensitivity represent two distinct ways these normal immune mechanisms cause tissue damage when they become excessive or misdirected. Unlike the rapid IgE-mediated reactions of Type I hypersensitivity, both Types III and IV operate on a delayed timescale — hours to days — and involve fundamentally different effector mechanisms.
Type III hypersensitivity centers on immune complexes — lattice-like networks formed when antibodies (typically IgG) bind soluble antigens. Normally, the body clears these complexes efficiently via complement receptors on red blood cells and phagocytes in the spleen and liver. Problems arise when complexes form in excess or in particular size ranges that resist clearance. These intermediate-sized complexes circulate and deposit in tissues with high blood flow and filtration — the glomeruli of the kidneys, the synovial membranes of joints, and the walls of small blood vessels. Once deposited, the complexes activate complement locally, generating C3a and C5a that recruit neutrophils. The neutrophils attempt to phagocytose the complexes but instead release their destructive enzymes into the surrounding tissue, causing vasculitis, glomerulonephritis, and arthritis. Classic examples include serum sickness (a systemic reaction to foreign proteins), the Arthus reaction (a localized injection-site response), and systemic lupus erythematosus, where autoantibodies against nuclear antigens form complexes that damage kidneys and joints.
Type IV hypersensitivity — also called delayed-type hypersensitivity (DTH) — is the only hypersensitivity reaction that does not involve antibodies at all. Instead, it is mediated entirely by T cells. When a sensitized individual encounters the antigen again, antigen-presenting cells process it and present peptides on MHC class II to memory CD4+ T cells. These T cells release inflammatory cytokines (IFN-γ, TNF-α) that recruit and activate macrophages over 24–72 hours, producing the characteristic firm, red induration rather than the wheal-and-flare of immediate reactions. The tuberculin skin test (PPD test) is the textbook demonstration: injected mycobacterial antigens provoke a measurable induration at 48–72 hours only in individuals previously exposed to *Mycobacterium tuberculosis*. Contact dermatitis — the rash from poison ivy or nickel jewelry — follows the same mechanism, with small chemical haptens binding to skin proteins to create neoantigens recognized by sensitized T cells.
The clinical distinction between these two types matters for diagnosis and treatment. Type III diseases show complement consumption, circulating immune complexes, and granular antibody deposits visible on immunofluorescence microscopy of biopsied tissue. Type IV reactions show mononuclear cell infiltrates (T cells and macrophages) with no antibody deposits. Treatment accordingly differs: Type III management targets antibody production and complement activation, while Type IV management focuses on suppressing T cell activation and macrophage recruitment with agents like corticosteroids or calcineurin inhibitors.