Type III Hypersensitivity Reaction

Overview

• Hypersensitivity reaction
  • A “hyper” or exaggerated response to what should be considered harmless environmental antigens
  • Types I, II, and III are immediate reactions occurring within 24 hours.
  • Type IV reaction develops over several days.
• Type III hypersensitivity reaction
  • Immune complex (IC)-mediated hypersensitivity: triggered by antigen-antibody (Ag-Ab) complexes deposited in tissues
  • Ag: intrinsic (part of the host) or extrinsic (exogenous source such as bacteria, virus)
  • As with type II hypersensitivity, cell injury is similar: Complement system leads to a reaction that produces cellular damage.
  • Unlike type II hypersensitivity, in type III reactions:
    • Antigens are not bound to cell surfaces. 
    • Ag-Ab complexes form in circulation.
    • Target of the immune response is not the tissue or cell. 
    • Target is the IC deposited in the tissue.

Pathophysiology

Physiology

• Immune complex formation normally results in antigen neutralization.
• The complement system reduces pathologic IC accumulation.
  • Antibodies (Ab) have 2 regions:
    • Fab region: attaches to antigens 
    • Fc region: interacts with complement and Fc-bearing receptor (FcR) cells
  • C1q: activates complement system and binds Ab Fc region, mediating IC clearance by FcR-bearing cells.
  • C3b: makes ICs soluble and tags them for phagocytosis (opsonization).

Pathogenesis

Immune complex formation: IC formed by the binding of Ag and Ab

Immune complex deposition

Immune complex deposition depends on:

• Physical properties of the IC: 
  • Affinity of Ab to complement, size, and charge of the IC 
  • Increased rate of IC formation → overwhelms clearing mechanism → IC freely circulate out to organs
• Antigen-to-antibody ratio: 
  • Low antibodies or excess antibodies → decreased effector activation
• Tissue-specific hemodynamics
  • ICs first localize within blood vessels → vasculitis
  • Common areas affected are “permeability”-susceptible tissues:
    • Glomeruli (nephritis)
    • Joints/synovium (arthritis)

Immune complex inflammatory reaction

• IC deposits activate the complement cascade.
• C3a initiates mast cell degranulation:
  • Histamine increases vascular permeability in the involved tissue. 
  • ICs enter tissue → normal tissue with IC becomes a target for inflammatory response
• C5a (chemoattractant) recruits neutrophils → release lysozymes and inflammatory mediators → cell death and tissue injury
• C3b opsonizes the tissue → phagocytosis and membrane attack complex (MAC)-mediated cell lysis
• Macrophages, natural killer cells → release lytic mediators and injure tissue cells
• Platelet aggregation can occur → micro thrombus formation

Clinical Presentation

Manifestations are affected by the route of entry, site(s) of IC deposition, and persistence of antigen(s).

Arthus phenomenon /Arthus reaction

• A locally injected antigen (e.g., immunization like Tdap) causes a localized reaction.
• Due to antigen excess and IC deposition on vascular walls
• Necrosis of affected tissues: pain, redness, induration, and edema at the site of injection
• Self-limited

Systemic lupus erythematosus (SLE)

• Antibodies directed against parts of the nucleus: antinuclear antibodies (ANA), a universal finding in SLE
• Antibodies to other parts of the nucleus: 
  • Histone (anti-histone Ab)
  • DNA (anti-dsDNA Ab)
  • Ribonucleoprotein (anti-RNP Ab) 
  • Extractable nuclear antigen/Smith antigen (Anti-Smith Ab)
• Other: Antibodies against phospholipids in cells (antiphospholipid Ab)
  • Present in 30%–40% of patients with SLE
  • Increased risk of thrombosis
• Ag-Ab complexes deposit in multiple areas:
  • Skin/mucocutaneous (malar rash, photosensitivity, oral ulcers)
  • Kidneys (glomerulonephritis)
  • Joints (arthritis)
  • Blood vessels (vasculitis, Raynaud’s phenomenon, blood clots)
  • Pleura (effusion)
  • Pericardium (pericarditis)
  • Blood cells (anemia, leukopenia, thrombocytopenia)
  • Central nervous system (strokes, seizures)

Post-streptococcal glomerulonephritis (PSGN)

• Reaction to nephritogenic antigens of group A beta-hemolytic streptococcus (GAS)
• Can be from streptococcal throat infection or skin infection
• Presentation: hematuria, proteinuria, hypertension, edema, and elevated creatinine

Serum sickness

• Reaction to foreign antisera (e.g., antivenom)
• Higher doses of administered agent more likely to result in a reaction
• 1–2 weeks after exposure: fever, rash, arthritis; proteinuria occurs with renal involvement

Hypersensitivity pneumonitis

• Extrinsic allergic alveolitis
• Antigen: a microbe, protein, or chemical
• IC deposition in alveoli, interstitium, bronchioli, and lung parenchyma
• Farmer’s lung: Ag from thermophilic molds on crops
• Bird fancier’s disease: Ag from intestinal mucin in droppings or feathers
• Note: can also be T-lymphocyte–mediated (type IV reaction)

Polyarteritis nodosa (PAN)

• Etiology mostly idiopathic but can be a reaction to hepatitis B virus surface Ag
• Medium-sized arterial inflammation → ↓ blood flow, ↑ thrombosis; spares the veins
• Kidneys: most commonly involved organ
• Presentation: 
  • Tender erythematous nodules, hypertension, renal insufficiency, and neuropathy
  • Some have abdominal symptoms (mesenteric arteritis)

Diagnosis and Management

Diagnosis

• Clinical history and findings (Arthus reaction, serum sickness often diagnosed clinically)
• Laboratory tests: 
  • CBC 
    • Anemia, thrombocytopenia, leukopenia: SLE
    • Eosinophilia: serum sickness, hypersensitivity pneumonitis
  • Metabolic panel 
    • Creatinine is abnormal in reactions involving the kidneys
  • Serologies and culture
    • Hepatitis panel for polyarteritis nodosa
    • Culture: streptococcal infection (only 25% of patients will have positive results because PSGN occurs weeks after the infection)
  • Complement levels 
    • Generally found in low levels in associated conditions
  • Antibodies
    • ANA, anti-dsDNA Ab, antiSmith Ab, anti-RNP Ab, antiphospholipid Ab: SLE 
    • PSGN: antistreptolysin O (ASO), streptozyme test
  • Urinalysis 
    • Proteinuria: SLE, PAN, serum sickness
    • PSGN: hematuria, proteinuria
  • Inflammatory markers 
    • Generally elevated C-reactive protein (CRP), erythrocyte sedimentation rate (ESR) during active inflammation
  • Imaging
    • High-resolution computed tomography (CT) (lung): hypersensitivity pneumonitis
    • Arteriography or CT/magnetic resonance angiography (MRA): for polyarteritis nodosa
    • X-ray: joint involvement
  • Surgical procedures 
    • Renal biopsy: for renal involvement
    • Skin biopsy: for cutaneous involvement
    • Bronchoscopy: for lung involvement

Management

• Remove or avoid offending agent
• Antihistamines, nonsteroidal anti-inflammatory drugs (NSAIDs) for symptom relief (rash, itching, joint pains)
• In reactions due to infection (PSGN), antibiotic therapy if infection is still present
• Control of complications such as hypertension (PSGN, PAN), edema (PSGN, SLE), airway symptoms (hypersensitivity pneumonitis)
• Glucocorticoids used in severe cases to suppress inflammation
• Therapeutic options for specific conditions:
  • Hypersensitivity pneumonitis: immunosuppressive therapy (mycophenolate, azathioprine)
  • SLE:
    • Antimalarials (hydroxychloroquine, chloroquine) 
    • Immunosuppressive therapy: mycophenolate, azathioprine, cyclophosphamide, rituximab
    • Long-term anticoagulation if with thrombosis: warfarin, low-molecular-weight heparin
  • PAN:
    • Methotrexate, a disease-modifying anti-rheumatic drug (DMARD)
    • Immunosuppressive therapy (cyclophosphamide, azathioprine)
• Dialysis for end-stage renal disease from SLE
• Organ transplantation:
  • Lung transplantation for advanced lung disease in hypersensitivity pneumonitis
  • Renal transplantation for end-stage renal disease in SLE