Two weeks after undergoing allogeneic stem cell transplant for multiple myeloma, a 55-year-old man develops a severely pruritic rash, abdominal cramps, and profuse diarrhea. He appears lethargic. Physical examination shows yellow sclerae. There is a generalized maculopapular rash on his face, trunk, and lower extremities, and desquamation of both soles. His serum alanine aminotransferase is 115 U/L, serum aspartate aminotransferase is 97 U/L, and serum total bilirubin is 2.7 mg/dL. Which of the following is the most likely underlying cause of this patient's condition?

Preformed cytotoxic anti-HLA antibodies

Proliferating transplanted B cells

Newly formed anti-HLA antibodies

A 23-year-old woman presents to her primary care provider complaining of diarrhea. She reports a 2 month history of 3-4 bloody stools per day as well as 10 pounds of unexpected weight loss. She has also developed intermittent mild gnawing lower abdominal pain. Her past medical history is unremarkable. She takes no medications and denies any drug allergies. Her family history is notable for colon cancer in her maternal aunt, rheumatoid arthritis in her paternal aunt, and Sjogren syndrome in her paternal grandmother. Her temperature is 99.1°F (37.3°C), blood pressure is 120/85 mmHg, pulse is 85/min, and respirations are 18/min. On exam, she has mild hypogastric tenderness to palpation. A stool guaiac test is positive. Flexible sigmoidoscopy demonstrates hyperemic and friable rectal mucosa. She is started on a medication to address her condition but presents to her physician one week later with a severe sunburn and skin itchiness following limited exposure to sunlight. Which of the following is the mechanism of action of the medication she received?

Dihydrofolate reductase inhibitor

A 28-year-old woman has a follow-up visit with her physician. She was diagnosed with allergic rhinitis and bronchial asthma at 11 years of age. Her regular controller medications include daily high-dose inhaled corticosteroids and montelukast, but she still needs to use a rescue inhaler 3–4 times a week following exercise. She also becomes breathless with moderate exertion. After a thorough evaluation, the physician explains that her medication dosages need to be increased. She declines taking oral corticosteroids daily due to concerns about side effects. The physician prescribes omalizumab, which is administered subcutaneously every 3 weeks. Which of the following best explains the mechanism of action of the new medication that has been added to the controller medications?

Prevention of binding of IgE antibodies to mast cell receptors

Inhibition of synthesis of interleukin-4 (IL-4)

Inhibition of synthesis of IgE antibodies

Selective binding to interleukin-3 (IL-3) and inhibition of its actions

Prevention of binding of interleukin-5 (IL-5) to its receptors

A 24-year-old woman presents to the emergency department because she started experiencing dyspnea and urticaria after dinner. Her symptoms began approximately 15 minutes after eating a new type of shellfish that she has never had before. On physical exam her breathing is labored, and pulmonary auscultation reveals wheezing bilaterally. Given this presentation, she is immediately started on intramuscular epinephrine for treatment of her symptoms. If part of this patient's symptoms were related to the systemic release of certain complement components, which of the following is another function of the responsible component?

Inhibition of kallikrein activation

A 35-year-old woman comes to the physician for the evaluation of fatigue over the past 6 months. During this period, she has also had fever, joint pain, and a recurrent skin rash on her face. She has smoked one pack of cigarettes daily for the past 15 years. Her temperature is 38.5°C (101.3°F), pulse is 90/min, and blood pressure is 130/80 mm Hg. Physical examination shows a facial rash that spares the nasolabial folds and several oral ulcers. Joints of the upper and lower extremities are tender with no reddening or swelling. Laboratory studies show anti-dsDNA antibodies. The patient is diagnosed with systemic lupus erythematosus and treatment of choice is initiated. Eight months later, the patient has weakness in her shoulders and hips. Examination shows slight weakness of the proximal muscles. Deep tendon reflexes are 2+ bilaterally. Laboratory studies show normal erythrocyte sedimentation rate and creatine kinase. Which of the following is the most likely underlying cause of this patient's symptoms?

Upper and lower motor neuron degeneration

Autoantibodies against postsynaptic acetylcholine receptors

Immunotherapies and checkpoint inhibitors — USMLE Lesson

Mechanism of Action - Taking the Brakes Off

T-cell activation requires two signals to attack. Cancer cells exploit inhibitory checkpoint pathways to apply the "brakes" on this process and evade the immune system.

Signal 1 (Accelerator): T-cell receptor (TCR) on the T-cell binds to the Major Histocompatibility Complex (MHC) on an antigen-presenting cell (APC) or tumor cell.
Signal 2 (Accelerator): Co-stimulatory protein B7 (CD80/86) on the APC binds to CD28 on the T-cell.

Inhibitory Checkpoints (Brakes):

CTLA-4: On the T-cell surface, it binds to B7 with higher affinity than CD28, preventing co-stimulation.
PD-1: On the T-cell surface, it binds to PD-L1 on tumor cells, inducing T-cell "exhaustion" and apoptosis.

Immune Checkpoint Inhibition Mechanism & Drug Targets

⭐ Cancers with high mutational burdens (e.g., melanoma, non-small cell lung cancer) often respond better to checkpoint inhibitors as they create more neoantigens for T-cells to recognize.

Checkpoint Inhibitors - The Major Players

Checkpoint inhibitors enhance the body's own immune system to fight cancer by blocking signals that suppress T-cell activity. Management of resulting immune-related adverse events (irAEs) typically involves corticosteroids.

Class	Drug(s)	Key Indications	Unique/High-Yield Toxicities
CTLA-4 Ab	Ipilimumab	Melanoma, RCC	High risk of irAEs: severe colitis, dermatitis, hypophysitis, hepatitis.
PD-1 Ab	Nivolumab, Pembrolizumab	Melanoma, NSCLC, RCC, Hodgkin Lymphoma	irAEs are common but often less severe. Pneumonitis, thyroiditis, myocarditis are notable.
PD-L1 Ab	Atezolizumab, Durvalumab	Urothelial Carcinoma, NSCLC	Similar profile to PD-1 inhibitors; risk of infusion-related reactions.

⭐ Pembrolizumab has a "tumor-agnostic" approval for any solid tumor with mismatch repair deficiency (dMMR) or high microsatellite instability (MSI-H).

Checkpoint inhibitors can cause widespread inflammation by unleashing T-cells. Onset varies from weeks to months after starting therapy. Common manifestations include:

Skin: Dermatitis, rash, pruritus (most common)
GI: Colitis, diarrhea (can be severe, bloody)
Liver: Hepatitis (asymptomatic ↑LFTs)
Lung: Pneumonitis (cough, dyspnea, hypoxia)
Endocrine: Hypophysitis, thyroiditis, adrenal insufficiency

Management Algorithm

⭐ Hypophysitis is a classic irAE of CTLA-4 inhibitors (e.g., Ipilimumab), presenting with headache and pituitary dysfunction.

High‑Yield Points - ⚡ Biggest Takeaways

Checkpoint inhibitors restore anti-tumor immunity by blocking signals like PD-1, PD-L1, and CTLA-4.

Key examples: Pembrolizumab (anti-PD-1), Ipilimumab (anti-CTLA-4), and Atezolizumab (anti-PD-L1).

Major side effects are immune-related adverse events (irAEs) like colitis, hepatitis, and pneumonitis, managed with corticosteroids.

CAR-T cell therapy engineers a patient's T-cells to attack cancer cells.

Watch for Cytokine Release Syndrome (CRS) and neurotoxicity with CAR-T; treat CRS with Tocilizumab (IL-6 inhibitor).

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