Learning Objective
By the end of this section, the learner will be able to explain the mechanisms of apoptosis, distinguish intrinsic and extrinsic pathways, identify key regulatory molecules (e.g., Bcl-2 family), and correlate dysregulation with disease.
Apoptosis
Apoptosis is an ATP-dependent programmed cell death process that eliminates unwanted or damaged cells in an orderly manner. It involves activation of caspases → controlled cellular dismantling with minimal inflammation.
Key Morphologic Features
- Cell shrinkage
- Cytoplasmic eosinophilia
- Chromatin condensation
- Membrane blebbing
- Nuclear pyknosis → karyorrhexis
- Formation of apoptotic bodies (later phagocytosed)
- Cell membrane remains intact → no significant inflammation
- DNA laddering (fragments in multiples of ~180 bp) is a sensitive marker
Mechanisms of Apoptosis
Apoptosis occurs via three major pathways, all converging on caspase activation.
Intrinsic (Mitochondrial) Pathway
Triggers
Occurs when regulatory survival signals are lost or when cellular injury occurs:
- Withdrawal of growth factors or cytokines
Example: ↓ IL-2 after immune response → apoptosis of T cells - DNA damage (radiation, toxins)
- Hypoxia
- Cellular stress
Molecular Control: Regulated by Bcl-2 family proteins:
| Group | Members | Function |
|---|---|---|
| Pro-apoptotic | Bax, Bak | Form mitochondrial pores |
| Anti-apoptotic | Bcl-2, Bcl-xL | Maintain membrane integrity |
Mechanism:
Bax/Bak activation → pores form → cytochrome C released → caspase activation → apoptosis.
Bcl-2 role:
- Blocks pore formation
- Prevents cytochrome C release
- Promotes cell survival
Clinical Connection
Follicular lymphoma (t14;18)
- overexpression of Bcl-2
- ↓ apoptosis
- lymphocyte accumulation (tumorigenesis)
Extrinsic (Death Receptor) Pathway
Triggered by receptor–ligand interactions.
Receptors and Ligands
- Fas (CD95) binding Fas-Ligand (FasL)
- TNF-α binds to the TNF receptor
Physiologic Role
Thymic negative selection of T cells
→ removal of self-reactive clones.
Disorder: Autoimmune Lymphoproliferative Syndrome (ALPS)
Caused by defective Fas-FasL signaling → failure of apoptosis of autoreactive lymphocytes.
Clinical features
- Lymphadenopathy
- Hepatosplenomegaly
- Autoimmune cytopenias
- Increased circulating lymphocytes
Perforin/Granzyme-B Pathway
Used by immune cells to kill infected or malignant cells.
Mechanism
| Cell Type | Role |
|---|---|
| Cytotoxic T cells | release perforin & granzyme |
| NK cells | same mechanism |
Sequence
- Perforin forms pores in the target cell membrane
- Granzyme B enters
- Granzyme activates caspases → apoptosis
Important in the elimination of:
- Virus-infected cells
- Tumor cells
- Transplant rejection responses
Summary Table
| Feature | Intrinsic | Extrinsic | Perforin/Granzyme |
|---|---|---|---|
| Trigger | DNA damage, stress, growth factor withdrawal | Ligand–receptor binding | Cytotoxic immune activity |
| Key Molecules | Bcl-2 family, cytochrome C | Fas/FasL, TNF receptor | Perforin, granzyme |
| Typical Example | Follicular lymphoma | ALPS | Killing virus-infected cells |
| Caspases Activated? | Yes | Yes | Yes |
| Inflammation | No | No | No |
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