Type III Hypersensitivity

Definition

Ag-Ab complex deposition → complement activation → inflammation. Onset ~6h. NOT tissue-specific (key difference from Type II) — deposits wherever filtration favours it (kidney, joints, vessels).

Aetiology (3 routes)

1. Persistent low-grade infection (weak Ab response, chronic complex formation)
2. Extrinsic environmental Ag (inhaled — Farmer’s lung, actinomycete hay)
3. Autoimmune (autoAb + self Ag — circulating e.g. IgA, or tissue e.g. DNA)

Pathogenesis (3 phases)

1. Formation — Ab (~1wk post-exposure) + circulating Ag → soluble complex
2. Deposition — uncleared complexes lodge in high-pressure filtration sites (glomeruli, joints, vessel walls, fenestrated endothelium)
3. Inflammation — classical complement activation: C3a → mast cell histamine/↑permeability; C5a → neutrophil chemotaxis; neutrophils/macrophages → lysosomal enzymes → fibrinoid necrosis + vasculitis (named by site: vasculitis/glomerulonephritis/arthritis). ↓serum C3 = disease activity marker (e.g. SLE flare).

Systemic vs Local

• Systemic = serum sickness — acute (single large dose, e.g. horse ATG → fever/rash/arthritis ~10d, resolves as cleared) vs chronic (repeated exposure, e.g. SLE)
• Local = Arthus reaction — antigen injected into skin of already-immunised host → local vessel-wall complex formation → oedema + haemorrhage ± ulceration, within hours

Examples

Immune complex GN (GBM or exogenous Ag, e.g. post-strep GN) · Goodpasture (also framed as Type II) · SLE (DNA/RNA Ag) · RA · Farmer’s lung · PAN/Wegener’s (± HBV Ag) · reactive arthritis (Yersinia) · Henoch-Schönlein purpura (viral Ag) · drug-induced vasculitis.

Clinical relevance

Type II vs III test: fixed tissue-specific Ag (II) vs circulating non-specific deposition (III) — resolves most confusion, explains why Goodpasture appears under both. ↓C3 = active SLE flare, not remission. Arthus reaction = real risk with repeat foreign-protein injections (vaccines/antitoxins) in previously sensitised patients.

Definition

Type III (immune complex-mediated, Arthus-type) hypersensitivity results from deposition of antigen–antibody complexes in tissue, followed by complement activation and an inflammatory reaction that produces cell injury. Onset is around 6 hours after antigen exposure — slower than Type I/II but still classed with the “immediate” antibody-mediated reactions rather than the truly delayed, cell-mediated Type IV.

Type III is not tissue-specific: unlike Type II, where antibody targets a defined antigen fixed to a particular cell or tissue, in Type III the antigen–antibody complex forms in the fluid phase (usually the circulation) and then deposits wherever anatomy and haemodynamics favour it — chiefly the kidney (glomeruli), joints (synovium) and small blood vessels, all sites where blood or fluid is filtered under pressure and immune complexes become concentrated. This is the key distinction to keep explicit between the two types.

Aetiology

Type III arises when antigen–antibody complexes are not efficiently cleared by the body’s normal mechanisms, through one of three routes:

1. Persistent low-grade microbial infection — a weak antibody response against a persisting bacterial or viral antigen leads to chronic complex formation that is never fully eliminated, so complexes instead deposit in vessel walls, glomeruli or joint tissue.
2. Extrinsic environmental antigen — inhaled antigens (from moulds, plants, animals) combine with antibody in alveolar fluid and deposit in the alveolar wall, as in Farmer’s lung (hypersensitivity pneumonitis from actinomycete-contaminated hay).
3. Autoimmune process — autoantibody against self antigen (circulating, e.g. IgA, or tissue-derived, e.g. DNA) forms immune complexes entirely from the body’s own components.

Pathogenesis

The pathogenesis unfolds in three phases:

1. Formation of immune complexes. Antibody forms roughly a week after antigen exposure and reacts with antigen still present in the circulation, generating soluble antigen–antibody complexes.
2. Deposition of immune complexes. Complexes that are not efficiently cleared by splenic/hepatic phagocytes instead deposit in tissue — preferentially organs where blood or fluid is filtered at high pressure (kidney glomeruli, synovium) and where fenestrated endothelium allows complexes to pass between endothelial cells.
3. Inflammation and tissue injury. Deposited complexes activate complement via the classical pathway (IgG/IgM Fc engaging C1): C3a stimulates mast cell histamine release, increasing vascular permeability and producing oedema; C5a is chemotactic for neutrophils and releases further pro-inflammatory mediators; accumulated neutrophils and macrophages release lysosomal enzymes and cytokines, producing the actual tissue destruction. The resulting histologic lesion is characteristically an acute necrotising vasculitis with fibrinoid necrosis of the vessel wall — vasculitis if in blood vessels, glomerulonephritis if in renal glomeruli, arthritis if in joints, the same underlying process named differently by site. Complement consumption during active disease lowers serum C3, a marker used clinically to track disease activity (e.g. in SLE).

Systemic versus Local Immune Complex Disease

• Systemic immune complex disease, historically characterised through serum sickness, a complication of receiving large amounts of foreign protein (originally diphtheria antitoxin raised in horses; today, agents such as horse/rabbit antithymocyte globulin used to deplete T cells in transplant recipients). Acute serum sickness, from a single large antigen dose, produces fever, rash, and arthritis roughly 10 days after exposure, resolving as complexes are phagocytically cleared. Chronic serum sickness results from repeated or prolonged antigen exposure and underlies diseases such as SLE, where persistent autoantibody responses continually regenerate fresh complexes.
• Local immune complex disease — the Arthus reaction. The experimental model: antigen injected into the skin of a previously immunised (already-antibody-positive) animal diffuses into the vessel wall at the injection site and binds preformed antibody, triggering the identical inflammatory sequence locally rather than systemically. Within hours the injection site develops oedema and haemorrhage, occasionally progressing to ulceration.

Examples

• Immune complex glomerulonephritis — antigen may be the glomerular basement membrane itself or an exogenous agent (e.g. post-streptococcal GN, streptococcal cell wall antigen “planted” in the GBM).
• Goodpasture syndrome — antigen is basement membrane (kidney and lung); note Goodpasture is more precisely a Type II mechanism at the antibody-binding step but is listed under both frameworks because complement/Fc-mediated inflammation (the Type II “inflammation” branch) closely resembles Type III tissue injury.
• Systemic lupus erythematosus — nuclear antigen (DNA, RNA), with anti-nuclear and anti-DNA autoantibodies forming circulating complexes that deposit in kidney, skin, joints and vessels (see Systemic Lupus Erythematosus and Autoimmunity).
• Rheumatoid arthritis — nuclear/other antigen-driven complex deposition in synovium.
• Farmer’s lung — actinomycete-contaminated hay as inhaled antigen.
• Polyarteritis nodosa and Wegener’s (ANCA-associated) granulomatosis — systemic vasculitis, in some PAN cases linked to hepatitis B antigen.
• Reactive arthritis — bacterial antigen (e.g. Yersinia).
• Henoch–Schönlein purpura — respiratory viral antigen implicated.
• Drug-induced vasculitis — the drug itself acts as antigen.
• Serum sickness and the Arthus reaction — as described above, the systemic and local prototype diseases respectively.

Clinical Relevance

• The single distinguishing question that separates Type II from Type III on an exam — “is the antigen fixed to a specific tissue (Type II) or does it form a complex that deposits non-specifically wherever filtration pressure favours it (Type III)?” — resolves the majority of borderline cases, including why Goodpasture syndrome is taught under both frameworks.
• Falling serum C3 as a marker of active immune-complex disease is a direct clinical application of the pathogenesis: complement is being consumed by ongoing complex deposition, so a falling C3 in a patient with known SLE signals a flare, not remission.
• The Arthus reaction is the conceptual bridge between experimental immunology and a real clinical entity: the same local vasculitis and oedema can occur at an injection site in an already-sensitised patient, which is why repeated injections of the same foreign protein (e.g. certain vaccines or antitoxins) carry a specific local-reaction risk in previously exposed individuals.

Diagram 1: Mechanism of Type III Hypersensitivity

Draw a single downward column of three phases, then branch into two side-by-side boxes for systemic versus local disease.

1. Formation — antibody plus circulating antigen forms soluble complexes, roughly a week after exposure.
2. Deposition — uncleared complexes lodge preferentially at high-pressure filtration sites.
3. Complement activation and inflammation — name C3a’s and C5a’s separate roles explicitly, and label the resulting lesion as fibrinoid necrosis/vasculitis.
4. Branch: systemic (serum sickness — fever, rash, arthritis, ~10 days) versus local (Arthus reaction — injection-site oedema/haemorrhage, hours, in an already-sensitised host).

Labels required

• C3a and C5a must be labelled with their distinct actions (C3a → mast cell histamine/permeability; C5a → neutrophil chemotaxis) rather than lumped as “complement activation,” since examiners test which fragment does which job.
• The systemic/local branch must specify that the Arthus reaction requires a previously sensitised host — it is not a first-exposure phenomenon, unlike the antigen exposure that initiates systemic disease.

Errors commonly made

• Describing Type III injury as direct antibody-mediated cell killing (confusing it with Type II) rather than as complement/neutrophil-driven inflammatory injury secondary to complex deposition.
• Treating serum sickness and the Arthus reaction as two unrelated diseases rather than as the systemic and local expressions of the identical three-phase mechanism.