delayed-type hypersensitivity

**Classification:** Type IV hypersensitivity (Gell and Coombs). It is cell-mediated, so it can't be passively transferred by serum. It can be transferred by T cells. No antibody or complement is involved.

**Two phases** 1. *Sensitization (first exposure):* Antigen is processed by antigen-presenting cells (e.g., Langerhans cells in skin) and presented on MHC II (to CD4+) or MHC I (to CD8+). Memory T cells are generated. This phase is often clinically silent. 2. *Elicitation (re-exposure):* Memory T cells recognize the antigen and release cytokines. The reaction peaks at 48–72 hours, which is why it is "delayed."

**Mechanisms** - *CD4+ Th1 pathway (macrophage activation):* Th1 cells secrete IFN-γ, which activates macrophages. Activated macrophages release TNF-α, IL-1, IL-12 and lysosomal enzymes, causing tissue damage. Chronic stimulation leads to **granuloma** formation, with epithelioid histiocytes and multinucleated giant cells. Caseous necrosis is seen in TB. Th17 cells also contribute through neutrophil recruitment. - *CD8+ CTL pathway:* Direct cytotoxicity via perforin/granzyme and Fas-FasL, causing apoptosis of target cells. Examples: contact dermatitis (hapten-modified self-proteins), transplant rejection, and viral hepatitis injury.

**Classic examples (high-yield)** - *PPD/tuberculin skin test:* Induration (not erythema) at 48–72 hours measures DTH to mycobacterial antigens. A false negative can occur with anergy (e.g., advanced HIV, sarcoidosis, overwhelming TB, immunosuppression). Interferon-γ release assays (IGRAs) are an alternative that is not affected by BCG vaccination. - *Allergic contact dermatitis:* Poison ivy/oak (urushiol), nickel, neomycin, latex (latex can also cause Type I), and hair dyes. Presents as an eczematous, vesicular, pruritic rash in the area of contact. Diagnosed by patch testing. - *Granulomatous diseases:* TB, leprosy (tuberculoid form has a strong Th1 response), sarcoidosis, Crohn disease, and fungal infections (histoplasmosis). - *Autoimmune:* Type 1 diabetes mellitus, multiple sclerosis, Guillain-Barré syndrome, Hashimoto thyroiditis (also has Type II and Type IV components), and rheumatoid arthritis (partly). - *Transplant:* Acute cellular rejection (T-cell mediated) and graft-versus-host disease. - *Drug reactions:* Stevens-Johnson syndrome/toxic epidermal necrolysis (CD8+ T cell-mediated; HLA-B*1502 with carbamazepine in Asian patients), DRESS, and morbilliform drug eruptions. - *Other:* Candida skin test (used to assess cell-mediated immunity), and the lepromin and Montenegro tests.

**Clinical significance/Management** - Treatment of contact dermatitis: avoid the allergen, use topical corticosteroids, and cool compresses for acute lesions. - Systemic corticosteroids are used for severe cases. T-cell-directed immunosuppressants (calcineurin inhibitors, antimetabolites) are used for transplant rejection and autoimmune disease. - Anti-TNF therapy (infliximab, adalimumab) impairs granuloma maintenance, which can reactivate latent TB. Screen with PPD or IGRA before starting.

**Board pearls** - Type IV is the only hypersensitivity type that is *T cell-mediated* and *not antibody-mediated*. - Mnemonic for the types: **ACID** — **A**naphylactic/Atopic (I), **C**ytotoxic (II), **I**mmune complex (III), **D**elayed (IV). - Th1 cytokines: IFN-γ, IL-2. IL-12 from macrophages drives Th1 differentiation. Defects in IL-12/IFN-γ signaling cause susceptibility to disseminated mycobacterial infection. - Histology: perivascular mononuclear infiltrate (lymphocytes and macrophages) in the skin reaction. - Contrast with Type I: Type I is IgE-mediated and occurs within minutes. Type IV occurs after 2–3 days.