Innate Immune system 2 Flashcards
What are pattern recognition receptor?
Part of innate immune system.
They recognise broad classes of molecules; they are invariant.
What are the two main classes
1) Membrane receptors: Toll and C-type lectin
2) Cytoplasmic receptors: NOD, DNA, RNA receptors
TLR history
In 1890- bacteria can cause inflammation, 1985- Toll protein discovered
1996- toll has two roles, development and antifungal
1997- breakthrough discovery- activation of immune system
1998/9- Without TLR4, mice do not respond to LPS.
What is sepsis?
In the case where there is a systemic infection there is excessive pro-inflammatory cytokines. A massive inflamation causes organ failure and death; the immune system is overactive and is fatal.
Decribe the TLR4 knock out experiment
Injection of bacterial endotoxin simulates infection and cytokines are triggered to cause inflammation. Where TLR4 is present in mouse it can function and causes endotoxic shock and death.
Where the TLR4 receptor is not present the mouse lives as it is not stimulated by LPS.
This discovery made it clear he innate immune response directly interacted and became activated with the pathogen.
What are the functions of TLR?
For pathogen killing:
1) Phagocytosis: uptake into a macrophage
2) Production of reactive oxygen species
For recruitment and activation of other immune cells:
3) Production of prostaglandins causing vasodilation
4) Production of chemokines
5) Production of pro-inflammatory cytokines
What role do TLRs have in diseases of pathogens
They are needed to activated host response to infection.
TLR3 mutation causes herpes virus; recurrent virus infections
IRAK4 mutation increase infections; even antibiotics at a young age result in death.
Tumours disrupt TLP to decrease killing of cancer cells.
What role do TLRs have in diseases of chronic inflammation: autoimmune
Unusual activation of TLR cause autoimmune disorders like Rheumatoid arthritis when there is too much activation.
SLE/Lupus when dead cells are not cleared and TLR binds to their secreted DNA
TLR is on B cells which may overstimulate B cell production of autoantibodies
What role do TLRs have in diseases of chronic inflammation
TLR activation of macrophage in adipose tissue cause diabetes
Too much TLR activation develops FOAM cells whcih are specialised macrophages in the atherosclerotic plaque causing cardiovascular disease
What is the background of TLR?
TLR are from IL1 family of interleukins; there are 10 TLR genes in humans with variation between species. The different types are in different locations. On the cell, the TLR must be in position to see pathogen but not host ligands.
What are the two types of TLRs?
1) Membrane TLRS
- TLR5 - responds to bacterial flagellin
- TLR1/2- Lipopeptides
- TLR2/6 -Lipopeptides
- TLR4- LPS
2) Endosomal TLRs respond to nucleic acids
- TLR3- double stranded DNA
- TLR7- Single stranded DNA
- TLR8- Single stranded DNA
- TLR9- CpG DNA where DNA is unmethylated.
What is the endogenous ligand for TLR called?
DAMPS (danger ass. molecular patterns) which can cause bad inflammation.
Describe structure of TLR
two dimeric extracelluar domains which contain leucine rich repeats and there crystal structure shows they look like a horse shoe and bind to ligand in the curve of the shoe; 2 LPS could bind to each domain.
2 intracellular domain where activation of signalling occurs; it contains a TIR domain (Toll receptor homology domain) which mediates interaction between TLR and adaptor proteins needed to start signalling.
How does Myd88 TLR signalling work?
Step 1: to recruit an adaptor protein varying depending on TLR. Myd88 either recruited to TLR directly or by the Mal protein.
Step 2: Myd88 has a TIR domain (and a death domain) Once ligand has bound TLR receptor, interaction between TIR on intracellular part of receptor and TIR part of Myd88.
Step 3:The death domain of Myd88 recruits protein called IRAK4 via IRAK4 death domain (also has a kinase domain)
Step 4: Downstream of this, IRAK4 recruits IRAK1 and IRAK2 via death domains where IRAK4 phosphorylates them which activates their kinase activity. IRAK1 has a scaffolding role; this step is the start of a signalling complex. IRAK2 has an INACTIVE kinase domain
Step 5: IRAK proteins mediate recruitment of TRAP6 leading to the formation of polyubiqitin chains, in particular chain with link on Lys63 and a linear chain where end terminus of one ubiqutin linked to C terminus of another. These chains are critical for downstream signalling
What are the adaptor proteins for the membrane TLRs?
TLR3: Myd88 and it can couple Myd88 with Triff
TLR2 and TLR4: couple Myd88 with Mal (second adaptor)
TLR4 also couples with Triff. Triff recruitment is mediated by Tram (TLR: has Mal, Myd88, Trif, Tram)
