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Difficulty: MediumCellular Injury and Adaptation

A 28-year-old woman is hospitalized for a severe flare of systemic lupus erythematosus, characterized by a malar rash, inflammatory polyarthritis, and new-onset proteinuria. Laboratory studies on admission reveal a serum creatinine of 1.8 mg/dL and an absolute lymphocyte count of 1,800/mm³. She is initiated on high-dose intravenous methylprednisolone therapy to manage the acute exacerbation. Five days later, her total leukocyte count remains stable, but her absolute lymphocyte count has decreased precipitously to 550/mm³. A peripheral blood smear shows normal red blood cell morphology, adequate platelets, and no abnormal lymphoid forms, schistocytes, or blasts. Which of the following best describes the fundamental cellular mechanism responsible for the rapid decline in this patient's lymphocyte count?

  1. DNA fragmentation by endonucleases with preservation of cell membrane integrityAnswer
  2. B
    Enzymatic digestion of cellular components accompanied by an acute inflammatory exudate
  3. C
    Intravascular fibrin polymerization and microthrombi formation leading to ischemic cell death
  4. D
    Depletion of intracellular ATP leading to failure of the sodium-potassium pump and cellular swelling
  5. E
    Excessive production of reactive oxygen species causing lipid peroxidation of the cell membrane

Answer

The rapid decline in lymphocytes is caused by apoptosis, which involves DNA fragmentation by endonucleases while maintaining cell membrane integrity.
The correct answer accurately describes apoptosis. Glucocorticoids are known to induce apoptosis in eosinophils, T lymphocytes, and B lymphocytes. The mechanism involves the alteration of gene transcription, leading to the activation of caspases and endonucleases. These enzymes cleave DNA into internucleosomal fragments. Crucially, the cell membrane remains intact during this process; the cell shrinks and packages its contents into apoptotic bodies, which are then phagocytosed by macrophages without eliciting an inflammatory response.

Step-by-Step Solution

1
Analyze the clinical presentation and medication history.
A patient with systemic lupus erythematosus experiences an isolated, severe drop in absolute lymphocyte count shortly after beginning high-dose methylprednisolone therapy.
Identifying the temporal relationship between the drug administration and the laboratory abnormality isolates the likely etiology.
2
Identify the expected pharmacologic effect of glucocorticoids on leukocytes.
Glucocorticoids cause demargination of neutrophils (leading to neutrophilia) but actively destroy lymphocytes (leading to lymphopenia) as part of their potent immunosuppressive effect.
Understanding drug mechanisms is necessary to bridge the clinical finding to the underlying cellular process.
3
Determine the specific cellular mechanism of this targeted cell death.
Glucocorticoids induce apoptosis in lymphocytes. This programmed cell death is characterized by cell shrinkage, chromatin condensation, endonuclease cleavage of DNA, and apoptotic body formation with intact membranes, avoiding inflammation.
Differentiating apoptosis from other forms of cellular injury (like necrosis or free radical damage) is required to select the correct histological and biochemical description.

Key Concept

Glucocorticoid-induced Apoptosis in Lymphocytes
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Topics

Cellular Injury and Adaptation

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