Type III and Type IV hypersensitivity reactions and their pathological presentations

1. Type III (immune-complex mediated)

Reaction induced by antigen–antibody (immune) complexes (IC). Antigens may be endogenous (self-DNA, histones) or exogenous (bacteria, virus). Complexes are normally cleared by phagocytosis; disease results when large numbers form and deposit in vessels/organs (systemic) or at the site of antigen entry (local).

Pathogenesis (3 steps):

1. IC formation in the circulation — antigen + antibody form complexes.
2. IC deposition in tissue beds — kidney, joints, small vessels.
3. Inflammatory reaction — deposited IgG/IgM activate complement → anaphylatoxins (C3a/C5a) → ↑ permeability + neutrophil/monocyte recruitment; platelet aggregation + Hageman factor → microthrombi & ischemia.

Morphology: necrotizing vasculitis, microthrombi, ischemic necrosis; vessel wall shows fibrinoid necrosis (smudgy eosinophilic protein deposition).

Organ	Lesion	Example
Joints (synovium)	Arthritis	Rheumatoid arthritis
Vessels	Vasculitis	Polyarteritis nodosa
Kidney	Glomerulonephritis	Membranous GN, SLE nephritis

Local IC disease — Arthus reaction: antigen injected into the skin of a pre-immunized host → IC precipitate locally (antibody excess) → acute IC vasculitis with edema, hemorrhage, ulceration; peaks 4–10 h after injection.

2. Type IV (cell-mediated / delayed)

Mediated by T cells, not antibodies. Two arms:

• Cytokine-mediated inflammation — CD4⁺ T cells → cytokines → recruit/activate macrophages & neutrophils → tissue injury.
• Cell-mediated cytotoxicity — CD8⁺ CTLs directly kill host cells.

2a. Delayed-type hypersensitivity (DTH)

Response to antigen in a previously sensitized host; classic example = tuberculin (PPD) reaction; mediated by CD4⁺ Th1.

1. First exposure → APC presents on MHC-II → IL-12 → generation of Th1 and memory T cells.
2. Re-exposure → recruitment of Th1/memory cells.
3. Th1 secretes IFN-γ → macrophage activation; PDGF/TGF-β → fibroblast proliferation + collagen.
4. Persistent stimulus → chronic inflammation → granuloma (epithelioid cells + giant cells + lymphocyte collar; older lesions fibrosed).

2b. T-cell mediated cytotoxicity

• CD8⁺ CTLs recognize intracellular peptides on MHC class I.
• Perforin–granzyme system: perforin opens the target membrane → granzymes enter → activate caspases → apoptosis.
• Important in solid-organ transplant rejection and implicated in T1DM.

	Type III	Type IV
Mediator	Immune complexes (IgG/IgM)	T cells (CD4 Th1 / CD8 CTL)
Timing	Hours (Arthus 4–10 h)	Delayed (24–72 h)
Histology	Fibrinoid necrosis, neutrophils	Mononuclear infiltrate, granuloma
Examples	SLE, PAN, post-strep GN, serum sickness	Contact dermatitis, TB/PPD, transplant rejection, T1DM

💡 High-yield: Type III = immune complexes → complement → neutrophils → fibrinoid necrosis (SLE, PAN, post-strep GN, serum sickness, Arthus). Type IV = T-cell mediated, delayed — CD4 Th1/IFN-γ → DTH/granuloma; CD8 CTL → perforin/granzyme → apoptosis (transplant rejection, contact dermatitis, T1DM).