10. Hypersensitivity reaction type 4

Core Concepts & Definition

• Definition: An exaggerated immune response mediated by antigen-specific T-cells (both CD4+ and CD8+), rather than antibodies.

• The "Delayed" Reaction: Unlike Type I which happens in minutes, Type IV takes 48 to 72 hours to develop after re-exposure to the antigen. This is the time required for T-cells to be recruited to the site, secrete cytokines, and activate macrophages.

• Key Players: T-cells (Th1, Th17, and Cytotoxic CD8+ T cells), Macrophages, and Cytokines (especially IFN-gamma).

• Memory Hook (ACID): Type I = Anaphylactic, Type II = Cytotoxic, Type III = Immune complex, Type IV = Delayed.

Pathogenesis

Type IV hypersensitivity causes tissue damage through two distinct but related T-cell pathways.

A. CD4+ T-Cell Mediated Inflammation (Delayed-Type Hypersensitivity - DTH)

B. CD8+ T-Cell Mediated Cytotoxicity

A. CD4+ T-Cell Mediated Inflammation (Delayed-Type Hypersensitivity - DTH)

1. Sensitization Phase: Initial exposure to an antigen (e.g., mycobacterial proteins, contact chemicals) results in the activation of naïve CD4+ T cells, which differentiate into Th1 and Th17 effector cells.

2. Effector Phase (Re-exposure): Upon subsequent exposure, these memory T cells are recruited to the site and secrete specific cytokines:

   • IFN-gamma (Crucial Exam Point): The most potent macrophage-activating cytokine. It transforms resting macrophages into aggressive "epitheloid" cells that release destructive enzymes, ROS, and inflammatory mediators.

   • IL-17: Secreted by Th17 cells, recruits neutrophils to the site.

   • TNF: Promotes inflammation and increased vascular permeability.

3. Tissue Damage: The hyper-activated macrophages cause non-specific collateral tissue damage and persistent inflammation.

4. Granuloma Formation: If the antigen cannot be cleared (e.g., Mycobacterium tuberculosis), the body attempts to "wall it off." Activated macrophages fuse to form multinucleated giant cells, creating a nodule called a granuloma.

B. CD8+ T-Cell Mediated Cytotoxicity

T-cells directly kill the host's own cells.

1. Mechanism: CD8+ Cytotoxic T Lymphocytes (CTLs) recognize antigens displayed on MHC Class I molecules on the surface of target cells (e.g., viral antigens, or donor antigens in a transplanted organ).

2. Execution: The CD8+ T cells directly kill the target cells via two methods:

   • Release of perforins and granzymes (punching holes in the cell and inducing apoptosis).

   • Fas-FasL binding (the T-cell Fas Ligand binds to the target cell's Fas receptor, triggering the extrinsic apoptosis pathway).

High-Yield Clinical Examples

Exam Tip: Look for conditions involving skin contact, granulomas, or solid organ rejection.

• The Tuberculin (PPD / Mantoux) Test:

  • The classic prototype. Purified protein derivative (PPD) of M. tuberculosis is injected intradermally.

  • If the patient has been previously sensitized (has memory Th1 cells from prior TB infection or BCG vaccine), a firm, red induration peaks at 48-72 hours due to macrophage accumulation.

• Contact Dermatitis:

  • Caused by environmental chemicals (e.g., Urushiol in poison ivy/oak, Nickel in jewelry).

  • These chemicals act as haptens—they are too small to cause a reaction alone, but bind to host skin proteins to become immunogenic. Result: Vesicular, highly pruritic (itchy) rash at the site of contact 2-3 days later.

• Granulomatous Diseases:

  • Tuberculosis, Leprosy, Sarcoidosis, and Crohn's disease. These all involve chronic Type IV reactions leading to tissue remodeling and granuloma formation.

• Autoimmune Diseases:

  • Type 1 Diabetes Mellitus: CD8+ T cells destroy the insulin-producing beta cells in the pancreas.

  • Multiple Sclerosis: Th1 and Th17 cells attack the myelin sheath in the central nervous system.

  • Hashimoto Thyroiditis: T-cell mediated destruction of thyroid tissue.