Lecture 29 - Innate Immunity II Flashcards
Janeway’s proposed mechanism of innate immunity
Presence of PAMPS and PRRs
Deficiency with Janeway’s proposed model
Didn’t account for sterile inflammation (inflammation without a pathogen)
EG: Crohn’s disease
Solution to problem of sterile inflammation
DAMPS
Example of a DAMP
DNA when it is outside the nucleus
Fungi PAMPs
1)
2)
3)
1) Zymosan
2) Mannan
3) Beta-glycan
TLRs
1)
2)
3)
1) Germline-encoded PRRs
2) Always associated with membranes
3) Stimulation results in cytokine and chemokine release
MyD88
1)
2)
3)
1) Secondary messenger (intracellular) that all TLRs signal through
2) Exception to this is TLR3, which signals through TRIF
3) TLR4 can use either MyD88 or TRIF
Which secondary messenger to all TLRs except TLR3 signal through?
MyD88
Which secondary messenger does TLR3 use?
TRIF
TRIF
Secondary messenger used by TLR3.
TLR4 goes through either MyD88 or TRIF
Transcription factor used by TLRs
NF-kB
Generic TLR signal transduction 1) 2) 3) 4) 5)
1) TLR binds ligand
2) Intracellular TIR domain of TLR binds to MyD88 (except for TLR3, or sometimes TLR4)
3) Death domain of MyD88 stimulates other factors, which lead to a kinase cascade
4) IkB is phosphorylated, which makes it release NF-kB
5) NF-kB enters nucleus, acts as a transcription factor
TLRs expressed on the cell membrane 1) 2) 3) 4)
1) TLR2
2) TLR4
3) TLR5
4) TLR11
TLRs expressed in phagosomes or endosomes
1)
2)
3)
1) TLR3
2) TLR7
3) TLR9
TLR4 MyD88 dependent response
1) Release of IL-6
IL6 effects 1) 2) 3) 4) 5)
1) Liver releases acute phase proteins (C- reactive protein)
2) Contributes to Th17 differentiation
3) B cell differentiation
4) Increased costimulatory molecule expression
5) Systemic inflammatory responses (fever, fatigue)
TLR4 MyD88-independent response
IFN alpha and beta release
IFN alpha and beta effects 1) 2) 3) 4)
1) Inhibition of viral protein synthesis
2) Degradation of viral RNA
3) Inhibition of virus assembly
4) Increased costimulatory molecule expression
Useful clinical marker for bacterial infections
C reactive protein
Only bacteria stimulate CRP release
How does IL-6 stimulate fever?
Enters the brain, stimulates the thalamus
IRF
Interferon-releasing factor
Number of genes transcribed as a result of IFNa/b release
Over 1000
Effect of IFN deficiency
Herpes simplex becomes lethal
RLR 1) 2) 3) 4) 5)
1) Rig-I like receptors
2) Recognise viral RNA in the cytosol
3) Associate with mitochondria
4) Require MAVS as an adaptor molecule
5) Induce secretion of IFNa/b
Transcription factors activated by rig-I like receptor stimulation
IRF (interferon-releasing factor)
Examples of self-derived factors that can stimulate NLR/inflammasomes 1) 2) 3) 4) 5)
1) Amyloid-b
2) ATP
3) Glucose
4) Hyaluronan
5) Cholesterol crystals
Environmentally-derived factors that can stimulate NLR/inflammasomes 1) 2) 3) 4)
1) Alum
2) Silica
3) Asbestos
4) UV radiation
Sources of factors that can result in NLR/inflammasome stimulation
1)
2)
3)
1) Environmentally-derived
2) Self-derived
3) Pathogen-derived
Factors that can stimulate NLRP3
1)
2)
3)
1) Damaged mitochondria
2) Potassium efflux from cell (alterations in membrane potential can indicate membrane damage, DAMP)
3) Lysosome destabilisation
Factor that can stimulate NLRP4
Flagellin (when intracellular)
What in gout can stimulate inflammasomes?
Uric acid crystals in joints
How does an inflammasome activate pro-caspase 1?
Sterically
Shape of assembled inflammasome activates pro-caspase 1
TLR3 ligand
dsRNA
TLR3 ligand source
Virus, bacteria
TLR3 activation effects
IFNa/b
TLR5 ligand
Flagellin
TLR5 activation effects
IL-6 release (from NF-kB)
TLR9 ligand
cPg DNA
cPg DNA source
Viruses, bacteria
TLR9 activation effect
IL-12
IFNa/b
TLR11 ligand
Flagellin
TLR11 activation effect
IL-6 (NF-kB)
Membrane-associated TLRs 1) 2) 3) 4)
1) TLR3
2) TLR5
3) TLR9
4) TLR11
RIG-like receptor location
Cytosolic
RIG-like receptors
1)
2)
1) RIG-1
2) MDA-5
RIG-1/MDA5 ligands
dsRNA
RIG-1/MDA5 stimulation effect
IL-6
IFNa/b
NLRC4 stimulation effect
IL-1b
IL-18
IL-33
Receptors that detect flagellin
1) TLR5
2) TLR11
3) NLRC4
PRRs that lead to NF-kB-mediated IL-6 release when stimulated
TLR-5, TLR-11
