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M2M > Toll-like receptors > Flashcards

Toll-like receptors Flashcards

1
Q

What are toll like receptors?

A
  • a class of proteins that play a key role in the innate immune system
  • come from our germline
  • single, membrane-spanning, non-catalytic receptors usually expressed on sentinel cells such as macrophages and dendritic cells, that recognize structurally conserved molecules derived from microbes
  • Once these microbes have breached physical barriers such as the skin or intestinal tract mucosa, they are recognized by TLRs, which activate immune cell responses
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2
Q

Does TLR signaling turn on inflammation?

A

yes

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3
Q

How do innate cells respond to an infection?

A
  • phagocytosis
  • antimicrobials
  • cytokines and chemokines
  • antigen presentation
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4
Q

What are pathogen associated molecular patterns (PAMPs)?

A
  • components of the microbe

- recognized by PRRs

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5
Q

What are pattern recognition receptors (PRRs)?

A
  • recognize microbial PAMPs
  • include TLRs
  • distinguish self from non-self
  • can be secreted, on cell surface or intracellular
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6
Q

What are the functions of PRRs?

A
  • activation of pro-inflamatory signaling
  • opsonization
  • coagulation
  • apoptosis
  • complement activation
  • phagocytosis
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7
Q

What do toll like receptors recognize?

A

multiple structurally unrelated PAMPs

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8
Q

What is the TLR domain structure?

A

Extracellular - leucine-rich repeats (LRR)

Intracellular - Toll/interleukin-1 receptor domain

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9
Q

What TLR recognizes triacyl lipopeptide and what adapters are activated?

A
  • TLR1 and TLR2

- TIRAP and MyD88 -> inflammatory cytokines

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10
Q

What TLR recognizes diacyl lipopeptide and what adapters are activated?

A
  • TLR2 and TLR6

- TIRAP and MyD88 -> inflammatory cytokines

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11
Q

What TLR recognizes dsRNA and what adapters are activated?

A
  • TLR3

- Trif -> inflammatory cytokines and Type I IFN

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12
Q

What TLR recognizes LPS and what adapters are activated?

A
  • TLR4
  • TRAM and Trif -> inflammatory cytokines and Type I IFN
  • TIRAP and MyD88 -> inflammatory cytokines
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13
Q

What TLR recognizes ssRNA and what adapters are activated?

A
  • TLR7 and TLR8

- MyD88 -> inflammatory cytokines and Type I IFN

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14
Q

What TLR recognizes Flagellin and what adapters are activated?

A
  • TLR5

- MyD88 -> inflammatory cytokines

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15
Q

What is the bacterial component on gram-negative bacteria that stimulates innate immunity?

A

lipopolysaccharide (LPS)

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16
Q

What is the bacterial component on gram-positive bacteria that stimulates innate immunity?

A
  • lipoteichoic acid

- peptidoglycan

17
Q

What are innate genes induced by TLR signaling?

A
  • inflammatory cytokines
  • chemokines
  • antimicrobials
18
Q

What are adaptive genes induced by TLR signaling?

A
  • MHC

- co-stimulatory molecules

19
Q

What happens when a TLR binds to a ligand?

A
  • dimerization of extracellular LRR domains

- signaling by intracellular TIR domains

20
Q

Where are TLRs that recognize bacteria or fungi?

A

cell surface

21
Q

Where are TLRs that recognize DNA or RNA?

A

endosome

22
Q

Which TLR moves from the surface to the endosome?

A

TLR4

23
Q

Why are TLR3, 7, 8, 9 in the endosome?

A

intracellular localization facilitates recognizing viral DNA and ssRNA and prevents recognition of self - prevents autoimmune disease

24
Q

What makes sure TLRs are delivered to the right place?

A

Unc93b1

25
Q

Can mutations in genes that regulate TLR3 transport/localization affect human disease as well as mutations in TLR3?

A

yes, mutations in Unc93b cause the same disease as mutations in TLR3

26
Q

What transcription factors do TLR signaling activates?

A
  • NFκB
  • AP-1
  • IRF
27
Q

What are the two adaptor proteins of TLR signaling?

A
  • Trif
  • MyD88
  • build up signaling pathways
28
Q

What are the two TLR4 signaling pathways?

A

cell surface - Myd88 dependent

endosome - TRIF dependent -> delayed

29
Q

Describe the TLR4 signaling Myd88-dependent pathway.

A
  • LPS stimulates TLR4-MD2 dimerization
  • recruits Myd88
  • Myd88 recruits kinases (IRAK-4, IRAK-1, IRAK-2)
  • ligase Taf6 recruited -> activates MAPKKK TAK1
  • TAK1 activates IKK complex, which phosphorylates IκB
  • IκB is ubiquinated and degraded -> releases NFκB
  • NFκB translocates into the nucleus
30
Q

What are negative regulators for TLR4?

A

Many places where they can turn the pathway off

31
Q

What happens when IRAK-4 is mutated?

A
  • recurrent bacterial infections (because TLR4 pathway)

- no further infections after 8 yrs

32
Q

What are three TLR pathways that can be used as targets for treatment?

A

Agonists - enhancing immunity to infectious disease
- enhancing vaccine efficacy

Antagonists - treating inflammatory diseases

M2M (41 decks)

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