U01.04.003 Apoptosis

Apoptosis is a form of ATP-dependent programmed cell death crucial for maintaining cellular homeostasis. It is characterized by specific cellular changes and is mediated by intrinsic and extrinsic pathways, both of which activate caspases, leading to cellular breakdown.

Key Characteristics of Apoptosis

Cellular Changes:
- Cell shrinkage
- Chromatin condensation
- Membrane blebbing
- Formation of apoptotic bodies (subsequently phagocytosed)
Histological Features:
- Deeply eosinophilic cytoplasm
- Basophilic nucleus
- Pyknosis (nuclear condensation)
- Karyorrhexis (nuclear fragmentation)
- Intact cell membrane (minimal inflammation, unlike necrosis)
DNA Fragmentation:
- DNA laddering: Sensitive indicator, showing fragments in multiples of 180 bp.

Pathways of Apoptosis

Intrinsic (Mitochondrial) Pathway

Role:
- Involved in tissue remodeling during embryogenesis.
- Triggered by withdrawal of growth factors (e.g., IL-2 after immune response).
- Activated by injurious stimuli (e.g., radiation, toxins, hypoxia).
Regulation:
- Bcl-2 family proteins:
  - Proapoptotic: BAX, BAK
  - Antiapoptotic: Bcl-2, Bcl-xL
Mechanism:
- BAX and BAK form pores in the mitochondrial membrane.
- This results in the release of cytochrome C into the cytoplasm.
- Cytochrome C activates caspases, initiating apoptosis.
Clinical Relevance:
- Bcl-2 overexpression (e.g., in follicular lymphoma, t[14;18]) prevents caspase activation, leading to tumorigenesis.

Extrinsic (Death Receptor) Pathway

Mechanism:
- Triggered through two main pathways:
  1. Ligand-Receptor Interactions:
    - FasL binding to Fas (CD95)
    - TNF-α binding to its receptor
  2. Immune Cell-Mediated:
    - Cytotoxic T-cells release perforin and granzyme B
Role in Immune System:
- Fas-FasL Interaction:
  - Crucial for thymic medullary negative selection (elimination of self-reactive lymphocytes).
- Fas Mutations:
  - This leads to an increase in circulating self-reactive lymphocytes due to the failure of clonal deletion.
  - Associated with autoimmune lymphoproliferative syndrome.

Table: Comparison of Intrinsic and Extrinsic Pathways

Feature	Intrinsic Pathway	Extrinsic Pathway
Trigger	Withdrawal of growth factors, injurious stimuli	Ligand-receptor interactions, immune cell-mediated
Key Proteins	Bcl-2 family (BAX, BAK, Bcl-2, Bcl-xL)	Fas, FasL, TNF-α, Perforin, Granzyme B
Mitochondrial Involvement	Yes (cytochrome C release)	No
Clinical Relevance	Tumorigenesis in Bcl-2 overexpression	Autoimmune lymphoproliferative syndrome

Table: Comparison of Intrinsic and Extrinsic Pathways

Points to Remember

Apoptosis is a highly regulated process essential for removing damaged or unnecessary cells.
Both intrinsic and extrinsic pathways ultimately activate caspases, leading to cell death without causing significant inflammation.
Dysregulation of apoptosis can lead to diseases such as cancer and autoimmune disorders.

USMLE Step 1 Review Series

Curriculum

U01.04.003 Apoptosis

Key Characteristics of Apoptosis

Pathways of Apoptosis

Intrinsic (Mitochondrial) Pathway

Extrinsic (Death Receptor) Pathway

Table: Comparison of Intrinsic and Extrinsic Pathways

Points to Remember

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