Clearance of Pathogens
Removing pathogens by phagocytosis
-> Pathogen Dies
Killing infected cells via apoptosis or autophagy
-> Pathogen and or host dies
What is the purpose of clearing dead cells
Removing dead and or dying cells
A mechanism in T cell development and negative selection
Restoring immune cell populations to homeostatic baseline after and immune response (killing effetor cells and maintaining memory cells
killing cancerous cells
What happens after a cell is phagocytosed
it is either exocytosed or recycled
An apoptotic body is also known as a
membrane bleb
What are the two stages of clearence of a apoptotic cell
Apoptotic bodies and microparticles need to be cleared without the activation of the inflammatory response
two stages = recruitment, then recofnition and engulfment
How do phagocytes cooperate during the onset, progression and resolution of inflammation
They first increase pro-inflammatory signals
Increase the number of cells
Cell-cell signalling p
Compare and contrast the function of neutrophils nad macrophages for the onset of phagocytosis
see printout
What are the three types of cell death
Apoptosis
Autophagy
Necrosis
Apoptosis
Programmed cell death
Energy dependent process -> nuclear fragmentation
can be induced by a variety of stimuli bot intrinsic and extrinsic
leads to caspase activation
apoptotic cells are cleared by phagocytes
Which caspases are triggered by apoptosis
Caspase 3 and 7
Apoptosis leads to activation of caspase 3 and 7 and to cell death
Autophagy
“self-eating” way to digest parts of the cell
lysosomal degredation of cellular components -> vacolization
often prevents cell death, but can promote it
for degredation of large organelles and large plaques such as amyloid beta
Why do neurons undergo autophagy instead of apoptosis
Neurons dont regenerate
Necrosis
injured cells swell and burst
Release cellular contents into microenviroment -> DAMPs
Extrinsic pathways of apoptosis
death receptor engagement on cell surface
Intrinsic pathway of apoptosis
caused by internal cell stressors leading to mitochondrial disruption
Proteasome
cell garbage can for small proteins
digrated by protease
Autophagy is essential for immunity
only process to dispose of intracellular organelles and protien aggregates to large for degredation via the proteasome
Give an example of how autophagy is involved in multiple pathways
innate and adaptive
IFN and proinflammatory cytokine regulation
Interplay between autophagy and apoptosis
counterbalance and regulation
neutrophiles go straight to apoptosis -> no autophagy
Neurons dont do this -> need to survive and maintain themselves at all costs
this is usually done via cleavage of ATG
Cleavage of ATG
bypasses autophagy and goes straight to apoptosis
DNA damage response (DDR) functional groups (4x)
dont want mutations to be passed on
DDR has four functional groups:
- damage sensors
- signal transduction
- repair effectors
- arrest/death effectors
What do key signal tranducers of the DDR permit
integration with the innate immune system
Purpose of the Nuclear DNA damage sensing pathway
for dectection of nuclear pathogens, ss DNA and dsDNA genomic breaks
PARP
A PRR
poly(ADP-ribose) polymerase 1 is a nuclear sensor activated in response to DNA single stranded breaks or double stranded breaks (Both of which are DAMPS)
ATM
atacia telangiectasia mutatated is a DNA damage kinase
p53-IFI16-TRAF6 translocation
assists nuclear-to-cytosol signalling cascade
STING
is a DNA sensor adaptor which binds and activates TBK1
TBK1
kinase which promotes activation of innate immune transcripiton factors IRF3 and NFkB
DNA damage is a hallmark of both cancers and neurodegenerative disease
To die or not to die
inverse correlation of clinical comorbidities and gene expression patterns between cancers and neurodegenerative disease
What is the solution if both cell survival and cell death are both undesirable circumstances
for example in cancer, survial is not the solution and in neurodegeneration death is not the solution
What is the best remedy for DNA damage
?
Inflammaging
accumulation of damage over time
over time, not all DNA damage is repaired, this leads to an increase in inflammation
Early benifits vs late costs of the innate immune DDR
in early life, organismal priorities are shifted towards development, growth and reproductive fitness
-> DDR ensures protection of the organism from developmental abnormalities and pathogens
with aging, somme DNA damage is left unrepaired and there is greater genomic unstability
- > intensification of DDR and inflammation over time
- > part of inflammaging
Stranger Danger Model
Stranger = PAMPs
Danger = DAMPs
DAMPs increase over time as we age
Explain how cell death and clearence mechanisms play a key role in immune function
death and clearence mechanism to get rid of neutophils that have undergone apoptosis.
Done by macrophages
M1-> M2 differentiation
promotion of angiogenisis
Explain how this may control inflammation in health and disease states
?
The hidden self model
DAMPS are generally hidden from the immune system = no inflammatory response
Autophagy, apoptosis and phagocytosis ensure cell debris and DAMPs are cleared from tissues
Necrosis releases DAMPs into extracellular milieu, revealing them to the immune system
You can’t fight what you can’t see
-> apoptosis hides DAMPs from the immune system
What immune cells perform phagocytosis
neutrophils, macrophages, dendritic cells and B lymphocytes
Compare and contrast the cellular mechanisms behind:
- phagocytosis
- autophagy
- necrosis
- apoptosis
?
Explain how apoptotic bodies are involved in the Stranger-Danger and Hidden-Self models of immunity
?
Explain why cell death pathways need to occur in a coordinated fashion to minimize negative impacts on the host
?