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