Questions: Hypersensitivity Reactions: Types I–IV

Question 1

A patient receives a PPD (tuberculin) skin test. 48 hours later, a raised, firm induration appears at the injection site. Which mechanism is responsible?

• A. IgE-mediated mast cell degranulation causing histamine release
• B. IgG antibodies targeting cells at the injection site, triggering complement
• C. Immune complex deposition activating complement and recruiting neutrophils
• D. Sensitized Th1 cells releasing IFN-γ and activating macrophages at the site

Answer: (D)

The 48-72 hour timeline is the hallmark of Type IV (delayed-type) hypersensitivity — exclusively T cell-mediated, with no antibodies involved. Prior TB exposure generates sensitized Th1 cells; on re-exposure to PPD, these cells recognize the antigen, release IFN-γ, and drive macrophage activation and granuloma formation, producing the induration. The other options all involve antibodies (Types I, II, III) and would produce reactions within hours, not days.

Question 2

A patient develops autoimmune hemolytic anemia: recipient IgG antibodies bind to antigens on the surface of red blood cells, which are then destroyed by complement activation and phagocytosis. This is best classified as which type of hypersensitivity?

• A. Type I — IgE binds to mast cells and triggers immediate destruction
• B. Type II — IgG targets cell-surface antigens, leading to cytotoxic destruction
• C. Type III — IgG forms immune complexes that deposit in the vascular endothelium
• D. Type IV — cytotoxic T cells directly lyse the red blood cells

Answer: (B)

Type II is defined by antibodies (IgG or IgM) directed specifically against cell-surface or matrix-bound antigens. Destruction follows via complement (MAC formation, opsonization), ADCC (NK cells), or phagocytosis. The key distinguishing feature from Type III is that the antibody targets a specific cell — the immune response is directed at a cell surface, not formed as circulating complexes that randomly deposit elsewhere. Type I is IgE only; Type IV has no antibodies at all.

Question 3

Type IV hypersensitivity reactions require prior sensitization and do not involve antibodies.

• T. True
• F. False

Answer: True

Both parts are correct and represent key features that distinguish Type IV from Types I–III. Prior sensitization generates antigen-specific T cells (Th1 and CTLs); re-exposure triggers these cells to respond, but the mechanism involves T cell cytokines (IFN-γ) and direct cytotoxic killing — not antibodies. This is why Type IV is called 'cell-mediated' or 'delayed' hypersensitivity and takes 48–72 hours rather than minutes to hours.

Question 4

Serum sickness — the systemic reaction that can occur after injection of foreign proteins — is an example of Type I hypersensitivity because it produces widespread symptoms including urticaria, fever, and joint pain.

• T. True
• F. False

Answer: False

Serum sickness is the classic example of Type III (immune complex–mediated) hypersensitivity. After repeated foreign protein injection, IgG antibodies are generated; when antigen is still present, antigen-antibody complexes form in excess and deposit in vessel walls, glomeruli, and joints. Complement activation at these sites drives inflammation. Symptoms appear 1–2 weeks after exposure — the time needed to mount an IgG response and accumulate complexes. Type I would appear within minutes and is driven by IgE, not IgG.

Question 5

What is the key mechanistic distinction between Type II and Type III hypersensitivity, given that both involve IgG antibodies and complement activation?

Model answer: In Type II, IgG (or IgM) is directed against antigens fixed to the surface of a specific cell or tissue — the antibody targets the cell directly, and destruction follows via complement, ADCC, or phagocytosis at that cell's surface. In Type III, IgG forms soluble immune complexes with circulating antigen; these complexes then deposit non-specifically in vascular walls, glomeruli, or joint spaces, where they activate complement and recruit neutrophils, causing inflammation at the deposition sites rather than at a specific target cell.

The distinction matters clinically: Type II attacks a specific cell type (RBCs in hemolytic anemia, thyroid receptor in Graves' disease), while Type III produces diffuse inflammation wherever complexes happen to deposit (kidneys, vessels, joints in serum sickness or post-strep GN). This also explains the different timelines: Type II can occur within hours; Type III typically takes days to weeks for complexes to accumulate and deposit.