8. Hypersensitivity Type 2 Reaction

Core Concepts & Definition

• Definition: An immune reaction mediated by IgG or IgM antibodies binding directly to specific antigens located on the surface of cells or extracellular matrix components.

• Target Antigens: Unlike Type I (soluble allergens) or Type III (soluble immune complexes), the antigens in Type II are fixed to a cell surface or tissue. These can be:

  • Endogenous (Self) antigens: e.g., basement membrane proteins, receptors.

  • Exogenous antigens: e.g., a drug metabolite that attaches to a red blood cell membrane.

• The Key Players: IgG and IgM antibodies, the Complement System, and Phagocytes (macrophages/neutrophils).

Pathogenesis

1. Opsonization and phagocytosis

2. Complement and Fc receptor mediated inflammation

3. Antibody-mediated cellular dysfunction

A. Opsonization and Phagocytosis

The cell is marked for death and eaten.

• Mechanism:

  1. IgG or IgM antibodies bind to antigens on a target cell (usually a circulating blood cell).

  2. This "tags" the cell for destruction (a process called opsonization).

  3. The antibodies may also activate the complement cascade, depositing C3b on the cell surface (another powerful opsonin).

  4. Phagocytes (macrophages/neutrophils in the spleen and liver) recognize the Fc portion of the antibody or the C3b and devour the cell.

• Alternative Fate: Membrane Attack Complex (MAC) formation. Sometimes complement activation proceeds all the way to C5b-9, punching holes directly in the cell membrane causing osmotic lysis.

• High-Yield Examples:

  • Autoimmune Hemolytic Anemia (AIHA): Antibodies attack RBCs.

  • Immune Thrombocytopenic Purpura (ITP): Antibodies attack platelets.

  • Transfusion Reactions: Donor RBCs are attacked by recipient antibodies.

  • Hemolytic Disease of the Newborn (Erythroblastosis fetalis): Maternal anti-Rh IgG crosses the placenta and attacks fetal RBCs.

B. Complement- and Fc Receptor-Mediated Inflammation

Antibodies bind to a solid tissue bed, causing collateral damage via inflammation.

• Mechanism:

  1. Antibodies bind to fixed antigens on tissues (e.g., basement membranes).

  2. The classic complement pathway is activated.

  3. Complement byproducts C3a and C5a are generated. These are potent chemotactic factors that recruit neutrophils and monocytes.

  4. The recruited WBCs try to phagocytose the tissue, but they can't because it's fixed ("frustrated phagocytosis").

  5. They release massive amounts of lysosomal enzymes and Reactive Oxygen Species (ROS), destroying the host tissue.

• High-Yield Examples:

  • Goodpasture Syndrome: Antibodies against Type IV collagen in the basement membranes of the lungs and kidneys → hemoptysis and hematuria.

  • Acute Rheumatic Fever: Antibodies against streptococcal antigens cross-react with heart tissue (Molecular Mimicry).

  • Hyperacute Transplant Rejection: Preformed antibodies immediately attack the endothelium of the grafted organ.

C. Antibody-Mediated Cellular Dysfunction

Antibodies bind to a cell surface receptor and alter its function WITHOUT causing inflammation or cell death.

• Mechanism: The antibody acts as an agonist (stimulating the receptor) or an antagonist (blocking the receptor).

• High-Yield Examples:

  • Graves' Disease (Agonist): Autoantibodies bind to the TSH receptor on thyroid epithelial cells and continuously stimulate it → Hyperthyroidism.

  • Myasthenia Gravis (Antagonist): Autoantibodies bind to and block Acetylcholine (ACh) receptors at the neuromuscular junction → severe muscle weakness.