A 25-year-old woman presents to an urgent care center following a bee sting while at a picnic with her friends. She immediately developed a skin rash and swelling over her arm and face. She endorses diffuse itching over her torso. Past medical history is significant for a mild allergy to pet dander and ragweed. She occasionally takes oral contraceptive pills and diphenhydramine for her allergies. Family history is noncontributory. Her blood pressure is 119/81 mm Hg, heart rate is 101/min, respiratory rate is 21/min, and temperature is 37°C (98.6°F). On physical examination, the patient has severe edema over her face and severe stridor with inspiration at the base of both lungs. Of the following options, this patient is likely experiencing which of the following hypersensitivity reactions?

Type 1 - anaphylactic hypersensitivity reaction

Type 2 - cytotoxic hypersensitivity reaction

Type 4 - cell mediated (delayed) hypersensitivity reaction

Type 3 - immune complex mediated hypersensitivity reaction

A 60-year-old man who recently immigrated from South America schedules an appointment with a physician to complete his pre-employment health clearance form. According to company policy, a skin test for tuberculosis must be administered to all new employees. Thus, he received an intradermal injection of purified protein derivative (PPD) on his left forearm. After 48 hours, a 14-mm oval induration is noticed. The type of cells most likely present and responsible for the indurated area will have which of the following characteristic features?

They need thymus for their maturation.

They are rich in myeloperoxidase enzyme.

They play an important part in allergic reactions.

They have multiple-lobed nucleus.

Their half-life is 24–48 hours.

A 55-year-old man with a history of fatigue and exertional dyspnea presents to the urgent care clinic following an acute upper respiratory illness. On physical examination, his pulses are bounding, his complexion is very pale, and scleral icterus is apparent. The spleen is moderately enlarged. Oxygen saturation is 79% at rest, with a new oxygen requirement of 9 L by a non-rebreather mask. Laboratory analysis results show a hemoglobin level of 6.8 g/dL. Of the following options, which hypersensitivity reaction does this condition represent?

Type II–cytotoxic hypersensitivity reaction

Type III–immune complex-mediated hypersensitivity reaction

Type I–anaphylactic hypersensitivity reaction

Type IV–cell-mediated (delayed) hypersensitivity reaction

Type II and III–mixed cytotoxic and immune complex hypersensitivity reaction

A 31-year-old woman presents to her primary care provider to discuss the results from a previous urine analysis. She has no new complaints and feels well. Past medical history is significant for systemic lupus erythematosus. She was diagnosed 5 years ago and takes hydroxychloroquine every day and prednisone when her condition flares. Her previous urine analysis shows elevated protein levels (4+) and blood (3+). The urine sediment contained red blood cells (6 RBCs/high-power field). The treating physician would like to perform a renal biopsy to rule out lupus nephritis. What type of hypersensitivity is suggestive of lupus nephritis?

Type III, mediated by IgG antibodies

Type IV, mediated by IgG and IgM antibodies

Type IV, mediated by CD4+ T cells

Type I, mediated by IgE antibodies

Type II, mediated by IgG and IgM antibodies

You are working in the emergency room of a children's hospital when a 4-year-old girl is brought in by ambulance due to "difficulty breathing." The patient had been eating lunch on a school field trip when she suddenly complained of abdominal pain. Shortly thereafter, she was noted to have swelling of the lips, a rapidly developing red rash and difficulty breathing. In the ambulance her blood pressure was persistently 80/50 mmHg despite intramuscular epinephrine. In the course of stabilization and work up of the patient, you note an elevated tryptase level. What is the mechanism behind this elevated tryptase level?

Cross-linking of IgE on mast cells

IgM mediated complement activation

Antibody-antigen immune complexes

Cross-linking of IgG on mast cells

A 45-year-old woman presents to her primary care physician for knee pain. She states that she has been experiencing a discomfort and pain in her left knee that lasts for several hours but tends to improve with use. She takes ibuprofen occasionally which has been minimally helpful. She states that this pain is making it difficult for her to work as a cashier. Her temperature is 98.6°F (37.0°C), blood pressure is 117/58 mmHg, pulse is 90/min, respirations are 14/min, and oxygen saturation is 97% on room air. Physical exam reveals a stable gait that the patient claims causes her pain. The patient has a non-pulsatile, non-erythematous, palpable mass over the posterior aspect of her left knee that is roughly 3 to 4 cm in diameter and is hypoechoic on ultrasound. Which of the following is associated with this patient's condition?

Inflammation of the pes anserinus bursa

A 55-year-old woman presents with pain in both hands and wrists for several years. It is associated with morning stiffness that lasts for almost an hour. She has a blood pressure of 124/76 mm Hg, heart rate of 71/min, and respiratory rate of 14/min. Physical examination reveals tenderness and swelling in both hands and wrists. Laboratory investigations reveal the presence of anti-cyclic citrullinated peptide. Which of the following immune-mediated processes is responsible for this patient’s condition?

IgE-mediated immune responses only

Both type II and III hypersensitivities

Hypersensitivity reactions (types I-IV) for USMLE Step 2 CK: High-Yield Pathology Lessons

Type I HSR - Allergic Anarchy

Mechanism: Immediate (Allergic, Anaphylactic), IgE-mediated degranulation of mast cells & basophils.
Phases:
- Early (minutes): Antigen cross-links IgE → histamine release → vasodilation, edema.
- Late (hours): Eosinophils & inflammatory cells recruited → sustained inflammation.
Examples: Allergic rhinitis, asthma, systemic anaphylaxis.

⭐ Tryptase is a specific marker for mast cell activation and can be measured in the blood to help diagnose anaphylaxis.

Type II HSR - Cytotoxic Crisis

Mechanism: Antibody-mediated (IgG, IgM) destruction of cells or tissues. Antibodies bind to cell-surface or extracellular matrix antigens.
Key Pathways:
- Complement activation → MAC complex → cell lysis.
- Opsonization & phagocytosis by macrophages.
- Antibody-dependent cell-mediated cytotoxicity (ADCC) by NK cells.
Clinical Examples:
- Autoimmune hemolytic anemia, Goodpasture syndrome, Rheumatic fever.
- Receptor-specific: Myasthenia gravis (blocking), Graves' disease (stimulating).

Type II Hypersensitivity Mechanisms

⭐ The Coombs test is crucial for diagnosis. Direct detects antibodies bound to RBCs; indirect detects anti-RBC antibodies in the patient's serum.

Type III HSR - Complex Chaos

Mechanism: Antigen-antibody (IgG) complexes form in circulation → deposit in tissues (e.g., vessels, glomeruli) → activate complement.
Pathology:
- Complement (C3a, C5a) attracts neutrophils.
- Neutrophils release lysosomal enzymes → tissue damage (vasculitis, fibrinoid necrosis).
- Develops over 3-8 hours.
Clinical Examples:
- Systemic: SLE, post-streptococcal glomerulonephritis, serum sickness.
- Local: Arthus reaction (e.g., after a booster vaccine).

Immune Complex Deposition in Vasculitis

⭐ Serum Sickness: A classic drug-induced Type III HSR. Drugs act as haptens, forming immune complexes. Presents with fever, urticaria, arthralgia, and proteinuria 1-2 weeks post-exposure.

Type IV HSR - Delayed Drama

Mechanism: T-cell mediated (no antibodies); delayed onset (48-72 hrs).
Pathways:
- Sensitization: Antigen-presenting cells (APCs) prime naive T-cells.
- Elicitation: Re-exposure → memory Th1 cells release IFN-γ → activates macrophages → inflammation.
Clinical Forms: Contact dermatitis (poison ivy, nickel), tuberculin skin test (PPD), granulomas (TB, sarcoidosis).

Tuberculin skin test induration measurement

⭐ The PPD test for tuberculosis is a classic example; the diameter of induration (palpable hardening), not just erythema, is measured.

Comparative Review - Reaction Roundup

📌 ACID Mnemonic: Anaphylactic (I), Cytotoxic (II), Immune Complex (III), Delayed (IV).

Feature	Type I (Anaphylactic)	Type II (Cytotoxic)	Type III (Immune Complex)	Type IV (Delayed)
Mediator	IgE	IgG, IgM	Antigen-Ab Complexes	T-Cells, Macrophages
Onset	Minutes	Variable	4-10 hours	48-72 hours
Mechanism	Mast cell degranulation	Complement activation	Neutrophil recruitment	Cytokine-mediated inflammation
Examples	Asthma, Allergies	Goodpasture, AIHA	SLE, Serum Sickness	PPD test, Contact Dermatitis

High‑Yield Points - ⚡ Biggest Takeaways

Type I (Anaphylactic) is IgE-mediated; requires initial sensitization, then re-exposure causes mast cell degranulation.

Type II (Cytotoxic) involves IgG/IgM against fixed cell-surface antigens, leading to complement-mediated damage.

Type III (Immune Complex) results from deposition of circulating antigen-antibody complexes, causing vasculitis or nephritis.

Type IV (Delayed-Type) is T-cell mediated; Th1 cells activate macrophages, causing a reaction in 48-72 hours.

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