U01.04.003 Apoptosis

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Learning Objectives

Distinguish between the Intrinsic (Mitochondrial), Extrinsic (Death Receptor), and Perforin/Granzyme B pathways of apoptosis. Master the regulatory roles of the Bcl-2 family proteins and Caspases, and recognize clinical correlations such as Follicular Lymphoma and Autoimmune Lymphoproliferative Syndrome (ALPS).

1. Apoptosis: Mechanisms and Morphology

Apoptosis is an ATP-dependent, programmed cell death process that removes unwanted cells without inducing an inflammatory response. Key features include cell shrinkage, chromatin condensation (pyknosis), and the formation of apoptotic bodies that are silently phagocytosed by macrophages.

 

Feature Description
Morphology Deeply eosinophilic cytoplasm, basophilic nucleus, and intact cell membrane.
DNA Laddering Sensitive indicator; DNA fragments in multiples of 180 bp (size of a nucleosome).
Executioners Caspases (Cysteine-ASPartate proteases) that dismantle the cell.

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2. The Intrinsic (Mitochondrial) Pathway

This pathway is involved in embryogenesis and responses to cell stress (radiation, toxins). It is governed by the balance of the Bcl-2 family of proteins, which control the permeability of the mitochondrial membrane.

Protein Group Examples Action
Pro-apoptotic Bax and Bak Form pores in mitochondria โ†’ Cytochrome C release โ†’ Caspase activation.
Anti-apoptotic Bcl-2 and Bcl-xL Keep the membrane impermeable; prevent Cytochrome C release.

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3. Extrinsic and Perforin Pathways

These pathways are triggered by external signals, often as part of the immune response to infected or self-reacting cells.

Pathway Initiators Clinical Correlation
Extrinsic FasL to Fas (CD95) or TNF-ฮฑ to receptor. ALPS: Defective Fas-FasL โ†’ failure of clonal deletion โ†’ autoimmunity.
Perforin/Granzyme Cytotoxic T-cells and NK cells. Perforin creates holes; Granzyme B enters to activate caspases directly.

 

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High-Yield Mnemonics & Tips:

  • Bcl-2 Family: BAX and BAK are “Bad” for survival (pro-apoptotic). Bcl-2 is “Be Clever” and live (anti-apoptotic).
  • Follicular Lymphoma: $t(14;18)$ moves Bcl-2 (18) to the Ig Heavy chain locus (14), leading to overexpression and zero apoptosis in B-cells.
  • Fas/CD95: Think “Fas” stands for “F”ast “A”poptosis “S”ignal. Defective Fas causes ALPS (lymphadenopathy/splenomegaly).

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