PRRs and inflammation

Question 1

What are teh 2 steps in production of IL-1b?

Answer 1

expression of pro-IL-1b and then cleavage by a protease

Question 2

What is expression og pro-IL-1b regulated by?

Answer 2

syntehsis of its mRNA in a TLR dependent manner

Question 3

what protease cleaves IL-1b?

Answer 3

caspase 1

Question 4

What complex activates caspase-1?

Answer 4

inflammasome

Question 5

How do type I IFNs play a central role in antiviral reponses?

Answer 5

induce apoptotic cell death in virally infected cells, render cells resistant to virus infection; activate acquired immunity; stimulate haemotpoietic stem cell turnover and proliferation

Question 6

What happens when type I IFN receptors are activated?

Answer 6

phorphsorylation and nuclear translocation of ISGF3 (IFN stimulated gene factor 3)

Question 7

What is the function of ISGF3?

Answer 7

induces expression og protein kinase R and OAS

Question 8

What is the function of protein kinase R?

Answer 8

suppresses the proliferation of virus infected cells

Question 9

What is the function of OAS?

Answer 9

activates RNAse L which cleaves viral nucleotides to inhibit virus replication

Question 10

What suggests that cellular responses to TLR2 ligands differs depending on the cell type involved?

Answer 10

stimulation of TLR2 produces proinflammatory cytokines- not type I IFNs in macropahges in DCs however in inflammatory monocytes TLR2 activation did induce type I IFNs

Question 11

As well as LPS, what else does TLR4 bind to?

Answer 11

viral envelope proteins

Question 12

Which cells highly express TLR5?

Answer 12

DCs of the lamina propria in the small intensine

Question 13

what happens to LPDCs in resposne to flagellin?

Answer 13

induces B cells to differentiate into IgA plasma cels and differentiation of naive T cells into Th17 and Th1 cells

Question 14

Aside from DNA, what else does TLR9 response to?

Answer 14

hemozoin- produced by malaria parasite

Question 15

Which cells highly express TLR7 and TLR9?

Answer 15

plasmacytoid DCs

Question 16

What must happen to TLR9 when it is recruited from the ER to the endolysosome?

Answer 16

processing by proteases such as cathepsins B, K and L in order to recognise CpG DNA

Question 17

What is required fro the TLR7 recognition in the endosome?

Answer 17

endosomal acidification

Question 18

What induces trafficking of TLR7 and TLR9 from the ER to the endolysosome?

Answer 18

stimulation with ligands or infection by viruses

Question 19

What happens to ciruses that have entered the cytoplasm and delivers nucleic acids to the endolysosome?

Answer 19

engulfed by autophagosomes

Question 20

What is autophagy?

Answer 20

self-proteins and damaged organelles are degraded in double-membraned vesicles called autophagosomes

Question 21

What suggests that autophagy is important in TLR7 and TLR9 recognition?

Answer 21

absence of ATG5- a protein essential for autophagosome formation results in pDCs failing to produce type I IFNs

Question 22

What links the polyubiquitin chain created by TRAF6?

Answer 22

lysine 63 (K63)

Question 23

What happens to phosphorylated IkB?

Answer 23

degradation by the ubiquitin-proteasome system

Question 24

What is the difference between signalling of TLR7 and TLR9 in cDCs vs pDCs?

Answer 24

in pDCs actiavte IRF and type I IFNs whereas in cDCs, IRF1 is activated resulting in IFN-b gene expression

Question 25

What does TLR4 require for activating TRIF?

Answer 25

TRAM

Question 26

What are RLRs composed of?

Answer 26

2 N-temrinal CARDs; a central DEAD box helicase/ATPase domain and a C-terminal regulatory domain

Question 27

What is the difference between the dsRNA recognised by RIG-I and MDA5?

Answer 27

MDA5 detects long dsRNA

Question 28

Which part of hte RLR is responsible for binding to dsRNAs?

Answer 28

C-terminal regulatory domain

Question 29

Where does STING translocate from and to in response to dsDNA?

Answer 29

from the ER to the golgi apparatus

Question 30

What are the 3 members of the RLR family?

Answer 30

RIG-I, MDA5 and LGP2

Question 31

Which TLR are pDCs entirely reliant on for production of cytokines?

Answer 31

TLR7

Question 32

What type of T cell response does CpG unmethylated DNA induce?

Answer 32

strong Th1

Question 33

What protein functions as a general chaperone for trafficking for most TLRs?

Answer 33

gp96

Question 34

What is the funciton of MAL?

Answer 34

acts as a sorting adaptor that recruits MyD88 to TLR2 and TLR4

Question 35

Why does TLR4 activate the MyD88 pathway earlier than the TRIF pathway?

Answer 35

activates MyD88 at the plasma membrane but then undergoes endocytosis to the endosome where it forms a signalling complex with TRAM and TRIF

Question 36

What is significant about TLR4 signalling using MyD88 and TRIF pathways as compared to other TLRs?

Answer 36

TLR4 requires both pathways in order to induce inflammatory cytokine whilst other TLRs only need one

Question 37

Give an example of a negative regulator of TLRs?

Answer 37

TANK - TRAF6 ubiquinitation in both macropahges and B cells

Question 38

What is DAI?

Answer 38

a cytosolic sensor for dsDNA that augments production of type I inferferon

Question 39

Why is DAI not thought to be significant?

Answer 39

in DAI-deficiney mice, type I IFN response is intact

Question 40

Give examples of DAMPs which can stimulate TLRs?

Answer 40

degradation products of the ECM; heat-shock proteins and HMGB1

Question 41

What is HMGB1?

Answer 41

a nuclear non-histone protein released by nectoric cells or during inflammation

Question 42

What TLRs recognise HMGB1?

Answer 42

TLR2, TLR4 and TLR9

Question 43

Why are self nucleic acids not recognised by TLRs in endolysosomes?

Answer 43

degraded by serum nucleases