SN3 SHORT NOTE 5M ★ High-yield

Describe apoptosis with its morphology, pathways and significance.

Pathology · 2nd Professional — Para-Clinical

Definition

Apoptosis is a regulated, energy-dependent form of cell death in which a cell activates enzymes that degrade its own nuclear DNA and cytoplasmic proteins, without provoking inflammation.

Morphological Features

Cell shrinkage — dense cytoplasm with tightly packed organelles
Chromatin condensation — the most characteristic feature; peripheral crescentic aggregation beneath the nuclear membrane
Cytoplasmic blebbing and formation of apoptotic bodies, membrane-bound fragments
Rapid phagocytosis by macrophages and by adjacent cells
NO inflammation, because the membrane never ruptures
Affects single cells scattered among healthy neighbours

The Two Pathways

Feature	Intrinsic (mitochondrial)	Extrinsic (death receptor)
Trigger	DNA damage, loss of growth factors, misfolded protein, radiation	Fas ligand on Fas (CD95); TNF on TNFR1
Key regulators	Bcl-2 family — BAX and BAK promote, bcl-2 and bcl-XL inhibit	FADD adaptor protein
Critical event	Release of cytochrome C from mitochondria	Assembly of the death-inducing signalling complex
Initiator caspase	Caspase 9	Caspase 8
Executioner caspases	3 and 6	3 and 6
Chief role	The commoner pathway; development and homeostasis	Killing by cytotoxic T cells; deletion of self-reactive lymphocytes

Cytotoxic T lymphocytes also use a third route — perforin makes a pore and granzyme B enters and activates caspases directly
P53 is the central sensor of DNA damage: it arrests the cell in G1 for repair, and triggers apoptosis if repair fails — hence its name, "guardian of the genome"

Detection

Histology — shrunken, deeply eosinophilic cells with condensed chromatin; Councilman bodies in viral hepatitis are apoptotic hepatocytes
DNA electrophoresis — a "ladder" of fragments in multiples of about 180 base pairs
TUNEL assay labels the DNA strand breaks
Annexin V binds phosphatidylserine exposed on the outer leaflet — the standard flow cytometric method

CLINICAL PEARL

The DNA "ladder" is the fingerprint of apoptosis. Apoptotic endonucleases cut only in the linker regions between nucleosomes, so every fragment is a multiple of about 180 base pairs. Necrosis, where digestion is random, gives a smear. One gel distinguishes the two mechanisms.

Applied Aspects

Cancer — too little apoptosis: loss of p53 in over half of all human cancers; the t(14;18) of follicular lymphoma places bcl-2 under the immunoglobulin heavy chain promoter, so the cells accumulate because they fail to die
Autoimmunity — failure to delete self-reactive lymphocytes; Fas mutations cause the autoimmune lymphoproliferative syndrome
Neurodegeneration — too much apoptosis: Alzheimer, Parkinson and Huntington diseases, triggered by misfolded protein
HIV — CD4 lymphocytes are lost largely by apoptosis, both infected and uninfected cells
Most chemotherapy and radiotherapy work by inducing apoptosis, which is why p53-mutant tumours are relatively resistant, and why bcl-2 inhibitors are now in clinical use

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