USMLE Step 1 Immunology Questions: Hypersensitivity Reactions – Types II, III and IV

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Hypersensitivity reactions are one of the most reliable Immunology topics on USMLE Step 1. You need to match each clinical picture to its mechanism: IgE, antibody against cells, immune complexes or T cells. Pick your answer first, then open the explanation.

Question 1: Dark urine and swelling two weeks after a sore throat

An 8-year-old boy is brought to the physician because of puffy eyes and cola-colored urine. Two weeks ago he had a sore throat with fever. Blood pressure is 138/88 mm Hg. Urinalysis shows red blood cell casts. Serum C3 level is low, and anti-streptolysin O titer is elevated. Which of the following best describes the mechanism of his kidney disease?

A. IgE-mediated mast cell degranulation
B. Antibodies directed against the glomerular basement membrane
C. Direct cytotoxic T-cell attack on glomeruli
D. Deposition of antigen-antibody complexes with complement activation
E. Direct bacterial invasion of the kidney

Correct answer: D. Deposition of antigen-antibody complexes with complement activation

This is poststreptococcal glomerulonephritis, a type III hypersensitivity reaction. Antigen-antibody (immune) complexes deposit in the glomeruli and activate complement, which explains the low C3. It appears 1–3 weeks after a group A streptococcal throat infection (or 3–6 weeks after skin infection). Electron microscopy shows subepithelial “humps.” Other type III examples: serum sickness, Arthus reaction and lupus nephritis.

Why the other options are wrong:

  • IgE-mediated reactions (type I) cause allergy and anaphylaxis.
  • Anti-GBM antibodies (type II) cause Goodpasture syndrome, with linear IgG deposits and often lung hemorrhage.
  • Cytotoxic T cells (type IV) are not the mechanism of PSGN.
  • Bacterial invasion does not occur; the throat infection triggers an immune response.

Question 2: Fever and red urine minutes into a blood transfusion

A 60-year-old man undergoing surgery receives a unit of packed red blood cells. Within 10 minutes he develops fever, chills, back pain and hypotension, and his urine turns red. A clerical error is discovered: he is blood type O and received type A blood. Which of the following is the mechanism of this reaction?

A. Preformed IgM antibodies binding to red cell antigens, activating complement
B. IgE antibodies binding to donor plasma proteins
C. Immune complex deposition in small vessels
D. Donor T cells attacking recipient tissue
E. Donor antibodies against recipient leukocytes

Correct answer: A. Preformed IgM antibodies binding to red cell antigens, activating complement

This is an acute hemolytic transfusion reaction, a type II hypersensitivity reaction. The recipient has preformed anti-A IgM antibodies that bind the donor red cells and activate complement, causing intravascular hemolysis: fever, flank pain, hypotension, hemoglobinuria and possibly DIC. Stop the transfusion immediately. Other type II examples include autoimmune hemolytic anemia, Graves disease and myasthenia gravis.

Why the other options are wrong:

  • IgE against plasma proteins causes allergic or anaphylactic transfusion reactions (e.g., in IgA deficiency), with urticaria and wheezing rather than hemolysis.
  • Immune complex disease (type III) develops over days, not minutes.
  • Donor T cells cause transfusion-associated graft-versus-host disease, weeks later.
  • Donor anti-leukocyte antibodies cause TRALI (acute lung injury) or febrile nonhemolytic reactions.

Question 3: A skin test read two to three days later

A 26-year-old nurse has a tuberculin skin test as part of her annual employment screening. Purified protein derivative is injected into the skin of her forearm. Seventy-two hours later, there is a 14-mm area of induration at the site. Which of the following cells are primarily responsible for this reaction?

A. Mast cells and basophils
B. Neutrophils activated by immune complexes
C. Eosinophils
D. B cells producing IgG
E. Sensitized CD4+ T cells that recruit and activate macrophages

Correct answer: E. Sensitized CD4+ T cells that recruit and activate macrophages

The tuberculin (PPD) test is a classic type IV (delayed-type) hypersensitivity reaction. It is not antibody-mediated. Previously sensitized CD4+ Th1 cells recognize the antigen and release cytokines such as IFN-γ, which recruit and activate macrophages. The reaction peaks at 48–72 hours. Other type IV examples: contact dermatitis (poison ivy, nickel), graft rejection and multiple sclerosis.

Why the other options are wrong:

  • Mast cells and basophils drive type I reactions within minutes.
  • Neutrophils activated by immune complexes are typical of type III reactions.
  • Eosinophils are prominent in parasitic infections and the late phase of allergy.
  • B cells and IgG are not required for type IV reactions.

Key takeaways

  • Type II: antibodies against cell-surface antigens (e.g., hemolytic transfusion reaction).
  • Type III: immune complexes + complement, low C3 (e.g., poststreptococcal GN, serum sickness).
  • Type IV: T cell-mediated and delayed 48–72 hours (e.g., PPD test, contact dermatitis).

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Written and reviewed by Dr. Ray Makar, MD, dermatologist with 20 years of clinical practice. Last reviewed: October 2026. For exam preparation only, not medical advice.

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