9. Hypersensitivity reaction type 3

Core Concepts & Definition

• Definition: An immune reaction triggered by the formation and deposition of antigen-antibody complexes (immune complexes) in tissues, which then cause massive complement activation and destructive inflammation.

• Target Antigens: Unlike Type II hypersensitivity (where antigens are fixed to a cell surface), the antigens in Type III are soluble and free-floating in the blood or body fluids.

  • Exogenous: E.g., foreign proteins, infectious microbial antigens.

  • Endogenous: E.g., self-DNA or nuclear proteins (as seen in autoimmune diseases like SLE).

• The Key Players: Soluble IgG and IgM antibodies, Immune Complexes (Ag-Ab complexes), the Complement System, and Neutrophils.

The pathologic hallmark of T3 hypersensitivity reaction?

Acute vasculitis characterized by fibrinoid necrosis (tissue death where immune complexes and fibrin leak into the vessel walls, looking bright pink/eosinophilic on histology).

Pathogenesis

THREE PHASES:

The damage in Type III is entirely collateral. The immune system is trying to clear the complexes, but they get stuck in tissues and cause innocent bystander destruction.

Phase 1: Immune Complex Formation

• An antigen enters the circulation, and the body produces antibodies (usually IgG or IgM) against it.

• The antibodies bind to the soluble antigens in the blood, creating circulating immune complexes.

Phase 2: Immune Complex Deposition

• Normally, macrophages in the spleen and liver clear these complexes. However, if the complexes are of an intermediate size, or if there is an overwhelming antigen load, they evade clearance.

• These complexes get filtered out of the blood and deposit in specific capillary beds under high hemodynamic pressure or with filtration functions.

• Classic Deposition Sites:

  • Kidneys: Glomeruli (causing glomerulonephritis)

  • Joints: Synovium (causing arthritis)

  • Small Blood Vessels: Endothelium (causing vasculitis)

Phase 3: Inflammation and Tissue Injury

1. The deposited immune complexes activate the Classical Complement Pathway.

2. Complement cleavage products C3a and C5a (anaphylatoxins) are generated.

3. C5a acts as a powerful chemoattractant, calling massive numbers of neutrophils to the site of deposition.

4. The neutrophils attempt to phagocytose the complexes but cannot because the complexes are embedded in the basement membrane ("frustrated phagocytosis").

5. The neutrophils degranulate, releasing lysosomal enzymes and Reactive Oxygen Species (ROS), heavily damaging the underlying vessel wall or tissue.

Clinical examples: Systemic Immune Complex Diseases

• Serum Sickness:

  • The classic prototype.Immune system against foreign proteins in medications (like penicillin) or chimeric monoclonal antibodies (like rituximab).

  • Timeline: Symptoms occur 1 to 2 weeks after exposure (the time it takes to produce enough IgG to form complexes).

  • Symptoms: Systemic rash, fever, polyarthritis, and proteinuria (due to deposition in skin, joints, and kidneys).

• Systemic Lupus Erythematosus (SLE):

  • Autoantibodies are formed against endogenous soluble antigens (like host DNA and antinuclear proteins).

  • The resulting immune complexes deposit systemically, causing lupus nephritis, arthritis, and skin rashes.

• Post-Streptococcal Glomerulonephritis (PSGN):

  • Occurs weeks after a Group A Strep infection (pharyngitis or impetigo).

  • Strep antigens and antibodies form complexes that deposit in the glomerular basement membrane, causing hematuria and edema ("lumpy-bumpy" appearance on immunofluorescence).

Clinical examples: Localized Immune Complex Disease

The Arthus Reaction:

• A localized area of tissue necrosis resulting from acute immune complex vasculitis.

• Mechanism: Occurs when an antigen is injected locally (intradermally) into an individual who has already been hyperimmunized (has extremely high levels of circulating IgG against that antigen).

• Example: Severe pain, swelling, and localized necrosis at the site of a booster vaccine injection (e.g., a tetanus booster given too soon after the previous one).

The Critical Distinction: Type II vs. Type III

• Type II Hypersensitivity: The antibody binds directly to an antigen FIXED on a specific tissue. (e.g., In Goodpasture syndrome, the antibody explicitly targets the basement membrane).

• Type III Hypersensitivity: The antibody binds to a SOLUBLE antigen in the blood. The resulting complex floats around and happens to get stuck in a tissue, causing damage there. The tissue is an innocent bystander.