Apoptosis

this is a series of notes on general pathology, useful for undergraduate and post graduate pathology students. Notes have been prepared from standard textbooks and are in a format easy to reproduce in exams.

1. 1
Notes on apoptosis.. By Dr. Ashish Jawarkar
Contact: [email protected] Website: pathologybasics.wix.com/notes
General Pathology Notes (Robbins)
By Dr. Ashish Jawarkar

Chapter 1 : CELLULAR RESPONES TO STRESS AND TOXIC INSULTS:
ADAPTATION, INJURY AND CELL DEATH


TOPIC 1. APOPTOSIS
aka Programmed cell death

OVERVIEW
1. definition
2. causes – 1 physiologic 2 pathologic
3. morphology – 1 Light microscopy 2 Electron Microscopy
4. Mechanisms – 1. Initiation – a. Intrinsic pathway b. extrinsic pathway
2. Execution
3. Removal of dead cells
5. Disorders of dysregulated apoptosis


* Definition
1. a pattern of cell death
2. affecting single cells
3. marked by fragmentation into cell membrane bound apoptotic bodies,
Condensation of chromatin
4. these apoptotic bodies are eliminated by phagocytosis

* Causes of Apoptosis

Physiologic Pathologic
1.During embryogenesis – implantation,
organogenesis, involution and metamorphosis
1. DNA damage – due to radiation/hypoxia/
Anticancer drugs
2. Due to hormone withdrawl
- endometrial cycle
- ovarian follicular atresia at menopause
- breast after weaning
- prostate after castration
2. Accumulation of misfolded proteins – ER
stress - apoptosis
This is the basis of degenerative diseases of
the CNS
3. In homeostasis
- lymphocytes that recognize self antigens
- epithelial cells in intestinal crypts
- neutrophils and lymphocytes at the end
of immune response
3. Certain viral infections lead to cell death by
apoptosis – like adenovirus, HIV and hepatitis
4. Atrophy of parenchymal organs after duct
obstruction – pancreas, parotid, kidney
* Morphology

2. 2
Notes on apoptosis.. By Dr. Ashish Jawarkar
Contact: [email protected] Website: pathologybasics.wix.com/notes
LIGHT MICROSCOPY
Apoptotic bodies seen as
1. shrunken cell
2. no damage to plasma membrane
3. intensely eosinophilic cytoplasm
4. dense nuclear chromatin
5. no inflammation

ELECTRON MICROSCOPY
1. intact nuclear membrane
2. chromatin condensation under nuclear membrane
3. formation of cytoplasmic blebs

* Mechanisms
Initiation – execution – clearing of dead cells

INITIATION


INTRINSIC PATHWAY EXTRINSIC PATHWAY
(mitochondrial) (death receptor)

Cell injury due to
1. growth factor withdrawl Receptor-ligand
2. ROS interactions
3. Toxins (Fas, TNF receptor)
4. Protein misfolding
5. radiation

Adapter proteins
Activation of Apoptotic sensors (FADD)
(Bcl-2 family – Bim, Bid, Bad)

# by
Bcl regulators
Activation of Apoptotic activators (Bcl-2, Bcl-x, Mcl-1) Initiator caspases
(Bcl-2 family – Bax, Bak) (# of apoptosis) (Caspase 8,
Insert into mitochondrial membrane in human caspase 10)
and create channels



Mitochondrial cyto-c leakage

3. 3
Notes on apoptosis.. By Dr. Ashish Jawarkar
Contact: [email protected] Website: pathologybasics.wix.com/notes

Cyto c in cytoplasm


Cyto C binds to apaf-1 and forms
cytoC-apaf1 complex Executioner
Caspase
(Caspase 3&6)
complex activates initiator caspase 9
inhibited by
SMAC/DIABLO
(# of apoptosis)
caspase 9 activates executioner
caspase 3






Endonuclease activation Breakdown of cytoskeleton


DNA fragmentation




Formation of cytoplasmic blebs and apoptotic bodies



Phagocytosis of apoptotic bodies

Removal of dead cells
The apoptotic bodies are recognized by phagocytes by –
1. alterations in plasma membrane
2. thrombospondin is expressed on the outer leaflet
3. coatin with complements eg. C1q

* disorders of dysregulated apoptosis
1. disorders due to too little apoptosis
- cancer
- autoimmune disorders
2. disorders due to too much apoptosis
- neurodegenerative diseases