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PA8.1-2 | Immunity & Hypersensitivity Reactions — SDL Guide (Part 3)

Type IV Hypersensitivity — Delayed/Cell-Mediated

Four-panel immunology diagram showing Type IV hypersensitivity as a delayed antibody-independent T-cell response with CD4+ Th1 macrophage activation, granuloma formation, and CD8+ cytotoxic target-cell killing. — **Panel A:** APC, antigen, T lymphocyte, CD4+ branch, CD8+ branch, no antibody mediation, delayed onset 48–72 hours. **Panel B:** Dendritic cell, MHC II, naive CD4+ T cell, Th1 memory cell, IFN-gamma, local APC, activated M1 macrophage, lysosomal enzymes, reactive oxygen species, cytokines, tissue necrosis. **Panel C:** Persistent antigen, central necrotic area, epithelioid macrophages, multinucleate giant cells, lymphocyte rim, granuloma. **Panel D:** CD8+ cytotoxic T lymphocyte, target cell, antigen on MHC I, perforin, granzymes, apoptosis, transplant rejection, type 1 diabetes beta-cell destruction.

Type IV is the only hypersensitivity type that is antibody-independent — it is mediated entirely by T lymphocytes. It is called "delayed" because it takes 48–72 hours to develop (time required to recruit and activate antigen-specific T cells and macrophages).

Two major subtypes:

A. CD4⁺ T helper–mediated (Th1-driven, "classical" delayed-type hypersensitivity — DTH):
1. Sensitization: First antigen exposure → dendritic cells present via MHC II → naive CD4⁺ T cells differentiate into Th1 memory cells (IFN-γ producers)
2. Elicitation: Re-exposure → Th1 cells recognise antigen on local APCs → secrete IFN-γ → macrophage activation (classical activation: M1 phenotype)
3. Tissue damage: Activated macrophages release lysosomal enzymes, reactive oxygen species, and cytokines → tissue necrosis
4. Persistence: Inability to clear antigen → granuloma formation (epithelioid macrophages + multinucleate giant cells + rim of lymphocytes)

B. CD8⁺ cytotoxic T lymphocyte (CTL)–mediated:
1. CD8⁺ T cells recognise antigen on MHC class I of target cells
2. Release perforin/granzymes → direct killing of target cell
3. Examples: Transplant rejection (allograft cells display foreign MHC I), type 1 diabetes (CTL destroy pancreatic β cells)

Clinical examples of Type IV:

Disease	Antigen	Key mechanism
Tuberculin (Mantoux) test	PPD (mycobacterial protein)	CD4 Th1 → macrophage activation; induration at 48–72 h
Contact dermatitis	Haptens (nickel, poison ivy/urushiol, latex)	Hapten binds skin proteins; CD8 + CD4 response; vesicular rash
Tuberculosis granuloma	Mycobacterium tuberculosis (not cleared)	Persistent Th1 → macrophage activation → caseous necrosis granuloma
Transplant rejection (acute cell-mediated)	Allogeneic MHC	CD8⁺ CTL + CD4⁺ Th1 → graft cell destruction
Type 1 diabetes mellitus	Islet β-cell antigens (GAD, IA-2)	CD8⁺ CTL → β-cell destruction → absolute insulin deficiency
Crohn disease	Luminal microbial antigens	Th1/Th17 granulomatous transmural inflammation

Why 48–72 hours? Pre-formed antibody acts within minutes to hours (Types I–III). T-cell–mediated responses require antigen recognition, T-cell mobilisation, and cytokine-driven macrophage recruitment from bone marrow — this cellular cascade is inherently slower.

SELF-CHECK

A nurse who had BCG vaccination as a child has a Mantoux (tuberculin) test placed. She returns 72 hours later and has a firm, indurated area of 18 mm. This reaction is BEST described as:

A. Type I — IgE-mediated mast cell response to PPD antigen

B. Type II — IgG-mediated cytotoxic destruction of dermal cells

C. Type IV — CD4⁺ Th1 memory cell activation and macrophage-mediated induration

D. Type III — immune complex deposition in the dermis causing vasculitis

Reveal Answer

Answer: C. Type IV — CD4⁺ Th1 memory cell activation and macrophage-mediated induration

The Mantoux test is the textbook example of Type IV (delayed-type) hypersensitivity. PPD antigens are presented via MHC class II to CD4⁺ Th1 memory cells (created during BCG vaccination or prior TB exposure). Over 48–72 hours, Th1 cells release IFN-γ, activating macrophages that accumulate at the site, producing the firm induration (not just erythema). The firmness distinguishes DTH (cellular infiltrate + fibrosis) from the transient wheal-and-flare of Type I (which resolves in < 1 hour).

Comparison of the Four Hypersensitivity Types

A four-panel comparison diagram shows Type I, II, III, and IV hypersensitivity mechanisms, mediators, antigen locations, effector cells, and representative clinical examples. — **Panel A:** Type I Immediate / Anaphylactic hypersensitivity: soluble environmental allergen, IgE, Fc receptor, mast cell, degranulation, histamine, anaphylaxis or allergy example.. **Panel B:** Type II Antibody-mediated / Cytotoxic hypersensitivity: cell surface or ECM antigen, IgG/IgM, complement activation, opsonization, MAC, target cell injury or receptor dysfunction.. **Panel C:** Type III Immune complex hypersensitivity: soluble circulating antigen, IgG/IgM immune complexes, vessel or glomerular deposition, complement, neutrophils, inflammation.. **Panel D:** Type IV Delayed / Cell-mediated hypersensitivity: APC, antigen presentation, Th1 cell, CTL, macrophage activation, target cell killing, 48-72 hour delayed response..

Feature	Type I	Type II	Type III	Type IV
Alternate name	Immediate / Anaphylactic	Antibody-mediated / Cytotoxic	Immune complex	Delayed / Cell-mediated
Mediator	IgE	IgG, IgM	IgG, IgM	T cells (Th1, CTL)
Antigen location	Soluble environmental	Cell surface / ECM	Soluble, in circulation	Intracellular / cell surface
Effector mechanism	Mast cell degranulation	Opsonization, lysis, receptor dysfunction	IC deposition → complement → neutrophil	Th1 → macrophage activation; CTL → cytotoxicity
Key mediators	Histamine, leukotrienes	Complement, ADCC	Complement (C3a, C5a), neutrophil enzymes	IFN-γ, TNF, perforin/granzymes
Onset	Minutes (early); 4–8 h (late)	Hours	Hours–days	48–72 hours
Prototypic examples	Anaphylaxis, asthma, atopy	AIHA, Graves, MG, Goodpasture	SLE, serum sickness, post-strep GN	TB, contact dermatitis, transplant rejection
Transfer via	Serum (IgE)	Serum (IgG/IgM)	Serum (IC)	Cells (T cells)
Complement involved?	Yes (minor — C3a, C5a)	Yes (major — MAC + opsonins)	Yes (major — C3a, C5a)	No
Histological pattern	Eosinophils, mucosal oedema	Variable; specific (e.g., haemolysis)	Neutrophilic vasculitis, granular IF	Mononuclear cells, granulomas (Type IV-A)